The group of immune disorders which leads to the occurrence of hemophagocytic lymphohistiocytosis (HLH) syndrome presents a strange paradox in that patients with these conditions associate a dramatic immune response to infection with the failure to establish an effective immune response. During the last few years, significant progress was made in the characterization and the understanding of the molecular basis involved in these inherited immune disorders. The hemophagocytic lymphohistiocytosis syndrome which characterized the evolution of the Chediak-Higashi syndrome and the Griscelli disease results from defects affecting intracellular trafficking. A defective SH2 protein interacting with T lymphocyte intracellular signaling pathways is the cause of the X-linked lymphoproliferative disease, whereas at least three distinct genetic defects can lead to the familial hemophagocytic lymphohistiocytosis. The molecular characterization of these latter defects is in progress. This review summarizes the recent advances as well as their implications in the diagnosis and the understanding of the physiopathology of these disorders.