In this, the first issue of Nature Reviews Drug Discovery of 2005, we feature an Innovation article by Keith, Borisy and Stockwell that discusses how a focus early in the drug discovery process on identifying and optimizing the activity of combinations of molecules could result in the identification of more effective drug regimens. Such pioneering approaches might allay some of the criticism the pharmaceutical industry has recently faced about its lack of innovation in the development of therapeutics, as discussed in an Opinion article by Cohen. A review by Gottlieb highlights some further genuinely innovative drugs that have recently been developed to target the immune system in patients with psoriasis. The treatment of another immune disorder — rheumatoid arthritis — is the subject of this month's Analyst's Couch, in which current therapeutics for this disease are evaluated. Adverse drug events that are mediated by the immune system account for a small but significant proportion of hospital admissions and can be serious, even life-threatening. An understanding of the complex interactions that lead to these adverse events is therefore an important challenge in the development of new drugs, and the genetic aspects of these interactions are reviewed by Bugelski. A challenge of a different type is the effective integration of the vast amount of data, from different biological domains, that is generated by 'omics' and during drug discovery. As Searls argues, new methodological and even cultural approaches might be required to optimize the business value and scientific impact of data integration. Finally, in the first of our series of articles on model organisms in drug discovery, Zon and Peterson discuss the advantages of using zebrafish in several aspects of the drug discovery process, including target identification, disease modelling, lead discovery and toxicology.