Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome of immune dysregulation that is classified into primary and secondary forms. The standard of care is established with dexamethasone and etoposide, but there are currently no guidelines for refractory HLH or cases triggered by infection or malignancy. [1] We describe here a series of pediatric patients with malignancy-associated HLH (m-HLH) to discuss the complexities in the initial diagnostic considerations, the balance of therapeutic regimens and their toxicities, and the novel use of emapalumab and ruxolitinib in patients with refractory disease.