Computational approaches that'dock'small molecules into the structures of macromolecular targets and'score'their potential complementarity to binding sites are widely used in hit identification and lead optimization. Indeed, there are now a number of drugs whose development was heavily influenced by or based on structure-based design and screening strategies, such as HIV protease inhibitors. Nevertheless, there remain significant challenges in the application of these approaches, in particular in relation to current scoring schemes. Here, we review key concepts and specific features of small-molecule–protein docking methods, highlight selected applications and discuss recent advances that aim to address the acknowledged limitations of established approaches.