Until fairly recently, proteases were considered primarily to be protein-degrading enzymes. However, this view has dramatically changed and proteases are now seen as extremely important signalling molecules that are involved in numerous vital processes. Protease signalling pathways are strictly regulated, and the dysregulation of protease activity can lead to pathologies such as cardiovascular and inflammatory diseases, cancer, osteoporosis and neurological disorders. Several small-molecule drugs targeting proteases are already on the market and many more are in development. The status of human protease research and prospects for future protease-targeted drugs are reviewed here, with reference to some key examples where protease drugs have succeeded or failed.