Calciphylaxis, a rare and life-threatening condition, involves the calcification and occlusion of microvasculature, leading to tissue ischemia and necrosis. The pathophysiology of calciphylaxis remains complex, but it is often associated with derangements in calcium and phosphate metabolism, ultimately resulting in the deposition of calcium within small blood vessels. This process leads to compromised blood flow, tissue hypoxia, and subsequent skin necrosis and ulceration, often with catastrophic consequences. While calciphylaxis typically occurs in individuals with end-stage renal disease (uremic calciphylaxis), it can also afflict those without renal impairment (non-uremic calciphylaxis). Several risk factors predispose individuals to this condition, including diabetes mellitus, hyperparathyroidism, malignancies, warfarin-based anticoagulation, alcoholic liver disease, and autoimmune disorders. Understanding the etiology, risk factors, and clinical manifestations of calciphylaxis is critical for timely diagnosis and management to mitigate its devastating effects. Management includes sepsis control, wound debridement, and analgesic support. We report a case of penile calciphylaxis in a 58-year old male with a past medical history significant for end stage renal disease on hemodialysis, diabetes mellitus, and hypertension. The patient presented with a painful lesion on the glans penis which rapidly progressed to necrosis and gangrene with wet features. The patient refused partial penectomy and wanted conservative management with local wound debridement and antibiotics., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Shah et al.)