© 2014, Springer Science+Business Media New York. Macrophage activation syndrome (MAS), typically presenting beyond the first year of life, is an often lethal cousin of familial hemophagocytic lymphohistiocytosis (fHLH). Defects in natural killer (NK) cell and CD8 T cell cytotoxicity result in a pro-inflammatory cytokine storm, cytopenia, coagulopathy, and multi-organ system dysfunction. MAS can occur in association with infections (herpes viruses), cancer (leukemia), immune deficient states (post-transplantation), and in autoimmune (systemic lupus erythematosus) and autoinflammatory conditions (systemic juvenile idiopathic arthritis). The distinction between fHLH, the result of homozygous defects in cytolytic pathway genes, and MAS is becoming blurred with the identification of single or multiple mutations in the same cytolytic pathway genes in patients with later onset MAS. Here, we review the literature and present novel cytolytic pathway gene mutations identified in children with MAS. We study the inhibitory effect of one these novel mutations on NK cell function to suggest a direct link between fHLH and MAS.