Purpose: While advances in flexible ureteroscopes and disposable suction systems have led to questions about percutaneous nephrolithotomy’s (PCNL) role in stone management, these alternatives are often insufficient for complex cases. This review examines PCNL’s efficacy and safety in four difficult patient groups: those with urinary diversion, neuromuscular disorders, renal transplants, and congenital anomalies where less invasive modalities, including flexible ureteroscopy and extracorporeal shock wave lithotripsy (ESWL), are often insufficient. Methods: A systematic review was conducted according to PRISMA guidelines and registered in PROSPERO (CRD420251044426). PubMed and Cochrane Library databases were searched for studies no lower date limit, through December 31, 2024. Study selection and quality assessment (Newcastle-Ottawa Scale) were performed independently by multiple reviewers. The primary outcome was stone-free rate, while secondary outcomes included complication rates and clinical feasibility of PCNL in these patient groups. Results: A total of 28 studies with 1,014 patients were included. PCNL was performed following failed ESWL or ureteroscopy (URS) in 18% of cases and often achieved complete clearance where previous modalities had failed. Across all subgroups, stone-free rates ranged from 48.7% to 100%, with highest outcomes in renal transplants (91.4%) and anomalies (84–92%). Complication rates varied (6.7–50%), reflecting anatomical complexity. Modified techniques such as Mini-PCNL enhanced feasibility in select cases. Conclusion: PCNL remains the most effective option in complex stone cases where flexible ureteroscopy (fURS) or ESWL often fail, consistently achieving high clearance rates with acceptable morbidity in anatomically challenging patients. Rather than being replaced, PCNL continues to define the boundaries of what is possible in endourology’s most difficult scenarios. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.