Mammalian target of rapamycin (mTOR) inhibitors are used as potent immunosuppressive agents in solid-organ transplant recipients (everolimus and sirolimus) and as antineoplastic therapies for various cancers (eg, advanced renal cell carcinoma; everolimus, temsirolimus, ridaforolimus). Relevant literature, obtained from specific PubMed searches, was reviewed to evaluate the incidence and mechanistic features of specific adverse events (AEs) associated with mTOR inhibitor treatment, and to present strategies to effectively manage these events. The AEs examined in this review include stomatitis and other cutaneous AEs, wound-healing complications (eg, lymphocele, incisional hernia), diabetes/hyperglycemia, dyslipidemia, proteinuria, nephrotoxicity, delayed graft function, pneumonitis, anemia, hypertension, gonadal dysfunction, and ovarian toxicity. Strategies for selecting appropriate patients for mTOR inhibitor therapy and minimizing the risks of AEs are discussed, along with best practices for identifying and managing side effects. mTOR inhibitors are promising therapeutic options in immunosuppression and oncology; most AEs can be effectively detected and managed or reversed with careful monitoring and appropriate interventions.