Abstract Improved awareness of hemophagocytic lymphohistiocytosis (HLH) among clinicians has led to an increase in its diagnosis. Often diagnosis is made based on the HLH- 2004 criteria. While these criteria have considerable strengths, they lack specificity and may be fulfilled in the setting of many pro-inflammatory disorders. Genetic defects affecting cellular cytotoxicity cause familial (primary) HLH. On the other hand, secondary HLH is more a pathophysiologic process common to many conditions, rather than a singular disease entity. Improved genetic, immunologic, and functional testing have changed not only the way we diagnose HLH, but also how we treat it. In 2004, there were few active agents and regimens. In 2024, there are multiple safe and effective targeted therapies. We have begun to understand that routine and immediate use of etoposide-based therapy in secondary HLH is likely not appropriate, and emerging cytokine-directed therapies may be more rational interventions. Moreover, it is recognized that identifying and treating the driver of secondary HLH is at least as important as treating the cytokine storm and immune dysregulation. Unfortunately, over-reliance on, and narrow interpretation of, the HLH- 2004 criteria can lead to overdiagnosis, misdiagnosis, and unneeded exposure to drugs that can be harmful. It is important that clinicians understand the limitations of the current diagnostic paradigms for secondary HLH, and the shortcomings of reflexive use of etoposide-based therapy. Herein we will discuss the pros and cons of the current paradigm for the recognition, diagnosis, and treatment of secondary HLH.