The histiocytoses comprise a rare and incompletely understood group of diseases that are characterized by an abnormal proliferation of histiocytes, mononuclear phagocytic, and antigen-presenting cells belonging to the reticuloendothelial system. The two major types of histiocytoses, which often present during infancy and require significant medical attention, are Langerhans cell histiocytosis and primary hemophagocytic lymphohistiocytosis. Their clinical manifestations frequently overlap, complicating their distinction, but a prompt and accurate diagnosis is essential to deliver the optimal treatment and maximize the chances for a favorable outcome. For Langerhans cell histiocytosis, careful risk stratification is critical for the appropriate administration of therapy. Patients with good prognostic factors may need only observation as their disease spontaneously regresses or minimal intervention. Poor prognostic factors mandate more intensive treatment. Patients with primary hemophagocytic lymphohistiocytosis require chemotherapeutic induction of their disease into a state of remission followed by stem cell transplantation, which currently offers the only known cure. Improvements on current therapies for the histiocytoses will depend on continued advances in the understanding of these enigmatic diseases.