Activity cliffs are formed by structurally similar compounds having large potency differences. Their study is a focal point of SAR analysis. We present a first systematic survey of single- and multitarget activity cliffs contained in currently available bioactive compounds. Approximately 12% of all active compounds were involved in the formation of activity cliffs. Perhaps unexpectedly, activity cliffs were found to be similarly distributed over different protein target families. Moreover, only approximately 5% of all activity cliffs were multitarget cliffs. Importantly, we also found that only very few multitarget cliffs were formed by compounds having different target selectivity. In addition, ‘polypharmacological cliffs’, i.e., multitarget activity cliffs involving targets from different protein families, were also only rarely found. Taken together, our findings reveal that only approximately 2% of all pairs of structurally similar compounds sharing the same biological activity form activity cliffs but that, on average, approximately one of 10 active compounds is involved in the formation of one or two single-target cliffs of large magnitude (with at least 100-fold difference in potency). These compounds provide a rich source of SAR information and can be identified across many different target families.