Enzymes are molecules that have highly diverse structures and functions, and their roles in the fundamental processes of biology make them excellent drug targets for many diseases. This month, three articles focus on enzymes as therapeutic targets. Michael Jirousek and colleagues discuss the potential of protein tyrosine phosphatase 1B as a novel target for type 2 diabetes and obesity. The development of small-molecule inhibitors against this phosphatase presents many challenges. ATPases are a group of enzymes that are already well-established drug targets, but none of the approved drugs targets the nucleotide-binding site. Patrick Chène discusses how structural analysis of these molecules can give clues to designing inhibitors that will occupy this site. Phosphodiesterases (PDEs) convert cyclic GMP to its corresponding nucleotide, and David Rotella reviews how inhibitors of the PDE5 isoform are used to treat erectile dysfunction, giving the latest clinical and preclinical updates. Two articles focus on aspects of the implications of genomics and proteomics for drug discovery. In the first Perpective article, Andrew Hopkins and Colin Groom analyse the number of molecular targets that might be represented in the human genome. Clarifying the role of novel targets in diseased tissue is one topic discussed by Petricoin and colleagues, who describe the application of proteomic technologies in the clinic. Drug addiction is a mounting social problem that has remained relatively ignored by drug developers. Mary Jeanne Kreek and colleagues highlight the current approved treatments for addiction, and review the most promising areas for future drug development. Linked to this is the final Perspective article, in which Philippe Pouletty discusses the magnitude and breadth of drug and alcohol abuse, and the opportunities that this area represents for drug development.