The authors propose a definition for rational multiple medication use (MMU). They then discuss how levels of diagnostic sophistication, ranging from symptomatic to syndromic to pathophysiologic to pathoetiologic, affect the ability to use multiple medications rationally. Based on this concept of diagnostic sophistication, MMU can be conceptualized dimensionally. Thus, MMU ranges from highly evolved and substantially evidence-validated approaches based on an understanding of the pathophysiological and pathoetiological nature of a disease (e.g., anti-retroviral treatment for HIV, multi-modal treatment of various malignancies), to those based on an understanding of the pathophysiology of an illness (e.g., various treatment combinations used to treat Parkinson’s disease), to less evolved or less evidence-based medication combinations based on a syndromic diagnosis (e.g., such as are often used to treat bipolar disorder). By better understanding the principles involved in rational MMU, clinicians can optimize the treatment they provide their patients. (Journal of Psychiatric Practice 2013;19:54–61).