Systemic drugs with an associated element of risk are essential in managing many important dermatoses. This review identifies eight major drugs or drug groups used in dermatology that require systematic monitoring for adverse effects. The complete monitoring process is emphasized, including significant patient involvement in reporting key signs or symptoms that allow early diagnosis of many of these adverse effects. The concepts of "risk-risk" assessment and "critical toxicities" are defined, emphasizing their important role in maximizing drug benefits and safety. Drug-related risk factors, disease-specific risk factors, and patient characteristics or habits that increase the risks from systemic drugs are identified. Basic principles of monitoring for adverse effects, specific clinical features of the most important adverse effects, along with detailed monitoring guidelines for methotrexate, retinoids, dapsone, corticosteroids, and cyclosporine are presented.