Systemic drugs play an important role in the modern practice of dermatology. The purpose of this article is to review systemic therapies in the following categories: antifungals, immunosuppressants, retinoids, and biologic immunomodulators. We provide a historical perspective, summarize current clinical indications, and discuss novel mechanisms of action for each drug. Suggestions for dosing regimens and laboratory monitoring are given. To help clinicians safely implement these therapies in their practice, we review major adverse reactions and clinically important drug interactions of these systemic medications in dermatology.