In this month's Guide to Drug Discovery article, Mario Geysen and colleagues discuss the many challenges in applying combinatorial chemistry to drug discovery. With these kinds of chemistries massively increasing the number of compunds available, Han van de Waterbeemd and Eric Gifford review how in silico modelling might accelerate the discovery process by improving our ability to make early predictions of pharmacokinetics and toxicity. Another approach to the rapid gathering of pharmacodynamic and pharmacokinetic information is proposed by Graham Lappin and Colin Garner, who discuss microdosing as a new method of obtaining early data in humans. Improving the safety and efficacy of drugs by pegylation — the addition of polyethylene glycol chains — is reviewed by Milton Harris and Robert Chess. This issue also highlights the challenges behind the development of several drugs, new and old. Rod Flower gives an account of the issues that surrounded the identification of the mechanism behind arguably the most common drug in use, aspirin, and describes how this eventually led to the development of the next-generation cyclooxygenase inhibitors. This month's From the Analyst's Couch looks at the market for these and other pain-killing drugs. The recently-approved aldosterone-receptor antagonist eplerenone is the subject for Fresh From the Pipeline, which asks whether this drug will become as successful as previous blockbusters for hypertension. And Craig Jordan describes how tamoxifen became the gold standard for the treatment of oestrogen-receptor-positive breast cancer. Finally, David Miska asks whether critics are right to blame drug regulatory authorities for impeding the quest for new drugs, and asks whether we should in fact be taking a closer look at some of the obstacles that the industry has imposed on itself.