Hemophagocytic lymphohistiocytosis (HLH) is a disorder of excessive activation of T cells (most likely CD8+ T cells) that recruit and activate other immune effector cells, such as macrophages, to produce the clinical features of HLH. Interferon gamma (IFNγ) plays a central role in this pathologic inflammation, while other cytokines such as IL-6, IL-18, and IL-1 may contribute in certain situations or patients. Conventional therapy relies on etoposide, or sometimes anti–T cell antibodies (ATG or alemtuzumab), which deplete T cells globally (serotherapy) or target activated ones (etoposide). Corticosteroids, which act broadly against many aspects of inflammation, are also an important part of standard therapy. Targeted therapies in development for HLH target specific inflammatory mediators such as IFNγ, IL-6, IL-18, or IL-1. Signaling molecules engaged by some of these cytokines, including Janus kinases (JAKs), are being targeted as well.