Smallmolecule drugs are the foundation of modern medical practice, yet their use is limited by the onset of unexpected and severe adverse events (AEs). Regulatory agencies rely on postmarketing surveillance tomonitor safety once drugs are approved for clinical use. Despite advances in pharmacovigilancemethods that address issues of confounding bias, clinical data of AEs are inherently noisy. Systems pharmacology the integration of systems biology and chemical genomics;can illuminate drug mechanisms of action.We hypothesize that these data can improve drug safety surveillance by highlighting drugs with a mechanistic connection to the target phenotype (enriching true positives) and filtering those that do not (depleting false positives). We present an algorithm, the modular assembly of drug safety subnetworks (MADSS), to combine systems pharmacology and pharmacovigilance data and significantly improve drug safety monitoring for four clinically relevant adverse drug reactions.