Multicentric reticulohistiocytosis (MRH) is a rare systemic inflammatory granulomatous disease that primarily manifests clinically with severe erosive arthritis and widespread papulonodular skin lesions but can involve multiple other organ systems. Despite the fact that this condition can become aggressive, debilitating as well as deforming with significant detrimental consequences, the etiology of this disease remains poorly understood. Moreover, the fact that MRH is such an uncommon disease has created an obstacle in the path of adequate clinical trials that are needed for better understanding of this phenomenon and for the development of treatment options for this patient population. In this review, we will attempt to discuss the epidemiology, pathophysiology, clinical features, associated conditions, differential diagnoses, diagnostic workup, and available treatments of MRH with the hope of creating a better understanding of this very challenging yet elusive disease process.