This paper takes the position that detrimental drug-drug interactions (DDIs) involving antidepressants are clinically relevant. In doing so, it begins with a definition of the terms: drug-drug interaction, detrimental, and clinical relevance. It then discusses the issues of proof and provides an overview of the clinically relevant DDIs involving antidepressants. It also gives examples involving drugs besides antidepressants based on the premise that the underlying principles are applicable regardless of the therapeutic classes of the drugs involved.