Dual and triple activity-difference (DAD/TAD) maps are tools for the systematic characterization of structure-activity relationships (SAR) of compound data sets screened against two or three targets. DAD and TAD maps are two- and three- dimensional representations of the pairwise activity differences of compound data sets, respectively. Adding pairwise structural similarity information into these maps readily reveals activity cliff regions in the SAR for one, two, or three targets. In addition, pairs of compounds in the smooth regions of the SAR and scaffold hops are also easily identified in these maps. Herein, DAD and TAD maps are employed for the systematic characterization of the SAR of a benchmark set of 299 compounds screened against dopamine, norepinephrine, and serotonin transporters. To reduce the well-known dependence of the activity landscape on the structural representation, five selected 2D and 3D structure representations were used to characterize the SAR. Systematic analysis of the DAD and TAD maps reveals regions in the landscape with similar SAR for two or the three targets as well as regions with inverse SAR, i.e., changes in structure that increase activity for one target, but decrease activity for the other target. Focusing the analysis on pairs of compounds with high structure similarity revealed the presence of single-, dual-, and triple-target activity cliffs, i.e., small changes in structure with high changes in potency for one, two, or the three targets, respectively. Triple-target scaffold hops are also discussed. Activity cliffs and scaffold hops were also quantified and represented using two recently proposed approaches namely, mean Structure Activity Landscape Index (mean SALI) and Consensus Structure-Activity Similarity (SAS) maps.