Activity cliffs are formed by structurally similar compounds with significant differences in potency and represent an extreme form of structure–activity relationships discontinuity. By contrast, regions of structure–activity relationships continuity in compound data sets result from the presence of structurally increasingly diverse compounds retaining similar activity. Previous studies have revealed that structure–activity relationships information extracted from large compound data sets is often heterogeneous in nature containing both continuous and discontinuous structure–activity relationships components. Structure–activity relationships discontinuity and continuity are often represented by different compound series, independent of each other. Here, we have searched different compound data sets for the presence of structure–activity relationships continuity within the vicinity of prominent activity cliffs. For this purpose, we have designed and implemented a computational approach utilizing particle swarm optimization to examine the structural neighborhood of activity cliffs for continuous structure–activity relationships components. Structure–activity relationships continuity in the structural neighborhood of activity cliffs was relatively rarely observed. However, in a number of cases, notable structure–activity relationships continuity was detected in the vicinity of prominent activity cliffs. Exemplary local structure–activity relationships environments displaying these characteristics were analyzed in detail. Thus, the structure–activity relationships environment of activity cliffs must not necessarily be discontinuous in nature, and local structure–activity relationships continuity and discontinuity can occur in a concerted manner in series of structurally related compounds.