Polypharmacy and inappropriate prescribing practices lead to higher rates of mortality and morbidity, particularly in vulnerable populations, such as the elderly and those with complex medical conditions. Physical medicine and physiatrists face particular challenges given the array of symptoms treated across a spectrum of conditions. This clinical review focuses on polypharmacy and the associated issue of potentially inappropriate prescribing. The article begins with a review of polypharmacy along with relevant aspects of pharmacokinetics and pharmacodynamics in the elderly. The adverse effects and potential hazards of selected medications commonly initiated and managed by rehabilitation specialists are then discussed with specific attention to pain medications, neurostimulants, antipsychotics, antidepressants, antispasmodics, sleep medications, and antiepileptics. Of particular concern is the notion that an adverse effect of one medication can mimic an indication for another and lead to a prescribing cascade and further adverse medication events. Appropriate prescribing practices mandate an accurate, current medication list, yet errors and inaccuracies often plague such lists. The evidence to support explicit (medications to avoid) and implicit (how to evaluate) criteria is presented along with the role of physicians and patients in prescribing medications. A brief discussion of “medication debridement” or de-prescribing strategies follows. In the last section, we draw on the essence of physiatry as a team-based endeavor to discuss the potential benefits of collaboration. In working to optimize medication prescribing, efforts should be made to collaborate not only with pharmacists and other medical specialties but with members of inpatient rehabilitation teams as well.