Based on this new landscape, we propose to create a public-private partnership called Critical Assessment of Computational Hit-finding Experiments (CACHE) to benchmark computational approaches to finding small molecule hits for proteins. Modelled after CASP, CACHE will organize hitfinding challenges against selected targets and participants will use various computational methods to predict hits. However, unlike CASP, which was able to piggy-back on experiments being done in the structural biology community, CACHE must have an experimental arm testing predictions prospectively. Each challenge will typically include two testing iterations to enable refinement and forward application of predictive models. Upon completion of a hit-finding challenge, all data generated by CACHE, including all chemical structures, will be publicly available without restrictions on use.