Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome of immune dysregulation that has primary and secondary forms. HLH is classified based on underlying triggers of malignancy, infections, and/or autoimmune processes. Primary-HLH has a genetic etiology related to defects in cytotoxic T and NK cells. The established standard of care is dexamethasone and etoposide but no guidelines exist for refractory HLH or cases triggered by malignancy. [1] We describe three pediatric patients with malignancy-associated HLH (m-HLH) to discuss complexities in initial diagnostic considerations, balance of therapeutic regimens/toxicities, and novel uses of emapalumab and ruxolitinib in refractory disease patients.