Safety-related drug failures remain a major challenge for the pharmaceutical industry. One approach to ensuring drug safety involves assessing small molecule drug specificity by examining the ability of a drug candidate to interact with a panel of "off-target" proteins, referred to as secondary pharmacology screening. Information from human genetics and pharmacology can be used to select proteins associated with adverse effects for such screening. In an analysis of marketed drugs, we found a clear relationship between the genetic and pharmacological phenotypes of a drug's off-target proteins and the observed drug side effects. In addition to using this phenotypic information for the selection of secondary pharmacology screens, we also show that it can be used to help identify drug off-target protein interactions responsible for drug-related adverse events. We anticipate that this phenotype-driven approach to secondary pharmacology screening will help to reduce safety-related drug failures due to drug off-target protein interactions.