Assessment of pharmacodynamic (PD) drug interactions is a cornerstone of the development of combination drug therapies. To guide this venture, we derive a general pharmacodynamic interaction (GPDI) model for ≥2 interacting drugs that is compatible with common additivity criteria. We propose a PD interaction to be quantifiable as multidirectional shifts in drug efficacy or potency and explicate the drugs' role as victim, perpetrator or even both at the same time. We evaluate the GPDI model against conventional approaches in a data set of 200 combination experiments in Saccharomyces cerevisiae: 22% interact additively, a minority of the interactions (11%) are bidirectional antagonistic or synergistic, whereas the majority (67%) are monodirectional, i.e., asymmetric with distinct perpetrators and victims, which is not classifiable by conventional methods. The GPDI model excellently reflects the observed interaction data, and hence represents an attractive approach for quantitative assessment of novel combination therapies along the drug development process.