Flexible ureteroscopy (fURS) is a well-established procedure for treating multiple upper-urinary tract pathologies, particularly renoureteral lithiasis. Endoscopes have undergone significant advancements, including miniaturization, improved optics, and increased maneuverability. In addition, advancements in accessory instruments, such as the performance of laser fibers, guidewires, and extraction probes, have played a significant role in improving the overall performance of flexible ureteroscopy procedures. However, despite these advancements, unique circumstances can make achieving optimum results during flexible ureteroscopy challenging. These include congenital renal anomalies (horseshoe kidneys, ectopic kidneys, rotation anomalies), as well as the unique intrarenal anatomy (infundibulopelvic angle, infundibular length) or the specifications of the endoscope in terms of maneuverability (active and passive deflection). This review explored challenging scenarios during flexible ureteroscopy procedures in the pyelocaliceal system.