As polypharmacy becomes increasingly common in patients with kidney disease, drug-drug interactions (DDIs), the phenomenon of one drug altering the effect of another drug, grow as potential sources of preventable harm in this vulnerable population. The clinical impacts of DDIs are poorly understood, particularly in the hospital setting, where up to half of patients have acute or chronic kidney disease. Further, the potential for bidirectional relationships between kidney disease and DDIs—with kidney disease functioning as both an outcome of DDIs and a baseline factor that alters DDI severity—complicates epidemiologic study and necessitates novel methodologic approaches. We undertook three distinct but related projects that explored the bidirectional relationships between kidney disease and DDIs. First, we proposed and provided theoretical justification for a novel study design, the dual control design, which specifically addresses unique challenges that are posed by the study of pharmacodynamic DDIs. Second, we applied this novel design to determine the risk of acute kidney injury during concomitant exposure to nonsteroidal anti-inflammatory drugs and inhibitors of the renin angiotensin system during inpatient admission. Third, we conducted a retrospective, longitudinal cohort study of patients on inpatient warfarin therapy that that examined the effect of renal dysfunction on the magnitude of the known interaction between warfarin and amiodarone, which is mediated by CYP2C9 enzyme inhibition.