Conversion between anti-epilectic drugs (AEDs) is frequently necessary in epilepsy care, exposing patients to a risk of incurring adverse effects and reduced quality of life. Little practical guidance is available to practitioners to guide conversions between AED monotherapies, or in adding a new adjunctive AED into a polytherapy regimen. This article reviews the impact of adverse effects of AEDs on quality of life in epilepsy patients, then reviews several important patient-related factors such as age, gender, medical and psychiatric co-morbidities, and co-medications that must be considered when selecting AEDs and ensuring tolerable and safe AED conversions. Practical strategies for transitional polytherapy AED conversion are then considered in different commonly encountered clinical scenarios in newly diagnosed and refractory epilepsy care, including inadequate seizure control, intolerable adverse effects, or idiosyncratic safety hazards. Successful conversion between AEDs requires regular monitoring for patient-reported adverse effects and appropriately reactive adjustment of AED therapy to maximize patient quality of life.