The ecstasy of discovering a new hit from screening can lead to a highly productive research effort to discover new bioactive compounds. However, in too many cases this ecstasy is followed by the agony of realizing that the compounds are not active against the desired target. Many of these false hits are Pan Assay INterference compoundS (PAINS) or colloidal aggregators. Alarmingly, up to 80−100% of initial hits from screening can be artifacts if appropriate control experiments are not employed. Perhaps the largest single source of artifacts in early discovery is colloidal aggregation by small molecules. These particles, typically between 50 and 1000 nm in radius, nonspecifically adsorb protein, partially denaturing them. About two percent of molecules in a typical screening deck will aggregate at relevant concentrations, ensuring that hits reflecting colloid formation dominate in screens, both virtual and empirical, which do not control for them. Fortunately, molecules that act as aggregators can sometimes be recognized computationally and better still, this mechanism may be readily controlled experimentally.