As reviewed in this article, the patient with ESRD presents a number of unique management challenges. A rapidly increasing number of patients are receiving renal transplants and undergoing dialysis, making it necessary for the dental practitioner to have a thorough understanding of the special treatment considerations that arise. Conservative medical management is designed to slow the progression of the disease and ameliorate the clinical consequences. Dialysis and transplantation provide renal replacement to sustain life and allow for the medical and social rehabilitation of the patient. When considering transplantation, oral examination is an essential part of the preoperative evaluation. Elimination of pathologic entities and restoring patient function are essential before the transplant and the immunosuppressive drug regimen. Any oral symptom or sign of infection must be examined immediately and treated aggressively in an immunosuppressed transplant recipient. Patients receiving hemodialysis and those with transplants should be considered for antimicrobial prophylaxis before dental treatment that induces bleeding to protect the function and patency of the vascular access site and the transplant. Drug therapy may need to be adjusted, depending on the degree of chronic renal failure, the patient’s dialysis schedule, or the presence of a transplant. Therefore, the dentist must be familiar with the complexity of this interesting patient population and pay particular attention when prescribing and using various medications.