Ureteroscopy is the treatment of choice for small ureteral or renal calculi and for diagnosis of ureteral abnormalities suspicious for urothelial carcinoma. In certain scenarios ureteroscopy may be used to treat large stones or tumors when other more favorable treatment modalities are not possible. In such situations ureteroscopy can prove to be a challenging procedure. Specific patient anatomic and physiological characteristics can make even a simple ureteroscopy a difficult procedure. Such situations include surgically altered urinary tract anatomy, congenital anomalies and obesity. Pathologic and iatrogenic bleeding diatheses are examples of where pathophysiology can adversely affect the procedure. Finally, pregnancy is an example of where a normal physiologic condition can make diagnosis and treatment of urolithiasis difficult due to concerns for the fetus. In this review we will discuss the use of ureteroscopy in such challenging patient scenarios.