In contrast to designed polypharmacology that can result in efficient drugs for complex disorders, unintended drug promiscuity has detrimental contribution to side effects and toxicology. Characterization of promiscuous compounds enhances the understanding of complex interaction patterns and aids the design of compounds with broader selectivity against off-targets that has a major impact on medicinal chemistry outcome. In this Miniperspective we provide insights to the effect of physicochemical parameters on promiscuity. Information collected from recent, large-scale in vitro studies enabled us to discuss the relationships between physicochemical properties and promiscuity in detail. In light of these data, lipophilicity and basic character have the highest influence. On the basis of the accumulated knowledge, we propose the extensive use of pre- and postsynthesis metrics, as well as strict control of physicochemical properties during medicinal chemistry optimizations.