The literature reports approximately 300 cases of multicentric reticulohistiocytosis (MRH) worldwide, mostly women of Caucasian origin. MRH manifests as a symmetric erosive polyarthritis mimicking rheumatoid arthritis with the subsequent appearance of typical papulonodular skin lesions. The disease may rapidly progress towards mutilans arthritis in the majority of cases, but it generally remits spontaneously in 10 years. The only diagnostic hallmark for MRH is the observation at histology of numerous histiocytes and multinucleated giant cells and ground glass eosinophilic cytoplasm. Despite its rarity, clinical and pathogenetic challenging features characterize the condition. First, the differential diagnosis with other forms of arthritis and the frequent coexistence of neoplasms or autoimmune diseases warrant a careful evaluation of suspected cases. Second, data from isolated MRH cases are consistent in supporting a role for monocyte/macrophage cells and for an enhanced osteoclastic activity in the affected tissues. Third, beside anti-inflammatory treatments, promising reports suggest that biologics targeting TNF-alpha and bisphosphonates may prove beneficial in MRH. Based on these observations, we are convinced that our understanding of this rare condition may prove beneficial in mechanistic advancement for other more prevalent inflammatory conditions such as arthritidies and other bone diseases.