The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) - which is the only one still in clinical development - is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time-action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is even too short (see postprandial glycaemic excursions with test meals in the publication by Rosenstock et al. in The Lancet (1)). In the end a number of aspects are of relevance for the success of a given product; one key aspect is clearly the price. However, for patients also practical aspects (handling, need for regular pulmonary function test etc.) are of importance. We shall have to see how creatively MannKind will handle all such questions. Until now Al Mann and his colleagues were able to manage a number of challenges during the clinical development process successfully, so one can have hopes for the market success of TI. However, it is clear that at the same time, if TI fails like Exubera did before, this will be the end for pulmonary insulin in general. Not too many original publications presenting data from clinical trials were published in the last year when it comes to oral insulin (OI), nasal insulin or transdermal insulin developments; simply none with transdermal insulin. Also at the last international congresses not many studies about ARIA were presented. At least in part this might be still a reflection of the shockwaves that the failure of Exubera has sent out to pharmaceutical companies and venture capitalists; they are quite reluctant to invest in any of these developments. However, a considerable number of reviews (in some cases more than original papers!) were published about ARIA. These reviews are listed for completeness, but in most cases are not further commented. OI is still the area of research most companies are active in; however, in some cases it is not clear how active they really are (e.g. Diabetology). Nevertheless, at least some companies are quite active and progressed in their clinical development programme close to market approval, e.g. the large Indian company Biocon is in late phase 3 with IN-105 and the small Israel-based company Oramed is in phase 2b. It appears that other interesting OI developments (e.g. Diasome) were not very active in the last year; at least they have not published new study results. It is clear that for companies that produce insulin themselves (e.g. Biocon) the costs of the good are not of such relevance as for companies that have to buy it commercially. For the latter ones a low bioavailability/biopotency compared with SC insulin administration can be a real hurdle when it comes to the price of their product. Despite some publications about nasal insulin, the overall activity with this route of insulin administration appears to be low; the same holds true for transdermal insulin. Insulin pens have gained more scientific interest in recent years, which is also reflected by an increase in publications, starting from practically nil 10 years ago to a solid number of five to 10 papers per year nowadays. Besides ARIA there are also attempts to increase the speed of insulin absorption after injection into the skin by applying it not into the SC tissue but intradermally or by heating up the skin above the SC insulin depot. Reading a number of papers that were not included in this chapter because they do not present any clinical data but are novel developments tested only in animal experiments so far, the clear message is that there is definitely not a lack of creativity/imagination amongst scientists; each year a plethora of new ideas for insulin application show up. Unfortunately not too many make it towards a full clinical development. As long as there is not a single successful product on the market that is based on a given ARIA approach, this area of research will not mature. For many patients, avoiding the need for SC injections is attractive; however, as long as no clear 'advantage' can be demonstrated, reimbursement will be difficult to achieve. Living in the time of evidence-based medicine it is clear that 'relevant' clinical advantages must be proven. The question is what is relevant. Is it just an improvement in metabolic control (= decrease in HbA1c)? Can this also mean that more patients are willing to start insulin therapy earlier than with conventional SC insulin therapy? With TI we have a product that has improved pharmacological properties (also in comparison to Exubera) for coverage of prandial insulin requirements. Subsequently, in the clinical trials performed, postprandial glycaemic excursions were lower than with SC injection of RHI or rapid-acting insulin analogues. This only in part (if at all) results in an improved metabolic control in general (= lower HbA1c) (see below). The outlook for 2011 is that there are chances that we shall have an inhaled insulin product on the market. Probably also the first OI will be submitted to the regulatory authorities for market approval or will even be available in less regulated markets. In order to select all relevant publications about new ways of insulin delivery I performed a PUBMED search and also checked the table of contents of a number of journals that publish heavily in this area of research as well references in the publications I found for additional references. Selection of the manuscripts from all publications was predominately based on the fact whether they presented data from clinical studies or not. The selected studies were critically reviewed for novelty and appropriate study design etc. In some cases also reviews about a given topic were selected if they provide relevant novel insights.