It is widely accepted that both comedications and genetic factors may contribute to variation of drug response. Clinical decision support systems increasingly consider recommendations on drug– drug interactions (DDIs) during electronic prescribing, and some guidelines on drug–gene-interactions (DGI) have been implemented in drug labels. Potentially synergistically or antagonistically acting drug-drug-gene interactions (DDGIs) have hardly been considered. This Perspective article highlights examples and the complexity of DDGI, aiming to strengthen consideration into clinical decision support.