People with end-stage kidney disease (ESKD) who require chronic dialysis are often reliant on complicated medication regimens to manage their health conditions. Due to the complexities of the advanced kidney disease, underlying comorbidities, and special instructions, medication regimens for patients on dialysis put patients at high risk for medication therapy problems related to safety, effectiveness, appropriateness, and adherence. This article explores the factors that affect optimal medication use for people on dialysis, including the broader drug use system, and offers recommendations around medication reconciliation, medication review, deprescribing, and considering social determinants of health to improve medication management among patients with ESKD.