Purpose of Review <p>To survey recent literature exploring mechanisms, biomarkers, diagnostic tools, and clinical management of non-IgE-mediated drug hypersensitivity reactions.</p> Recent Findings <p>Immediate hypersensitivity reactions to medications have historically been classified by IgE-mediated mast cell degranulation. However, recent evidence supports a much broader spectrum of endotypes that vary in both mast cell- and IgE-dependence. Most recent attention has focused on IgE-independent mast cell-dependent mechanisms, which include the Mas-related G protein-coupled receptor X2, as well as complement-driven pseudoallergic and IgG-mediated mechanisms. These mast cell degranulation reactions can manifest in clinically identical phenotypes, and distinguishing biomarkers or diagnostic tools is currently limited. Differences across these endotypes are emerging, as evidenced by recent skin test-dose response characteristics for vancomycin, providing an important model to define these underlying mechanisms further. This mechanistic understanding will be critical to developing precise diagnostic and management strategies for immediate hypersensitivity reactions to medications.</p> Summary <p>While our understanding of immediate non-IgE-mediated hypersensitivity reactions has expanded rapidly over the last decade, current paradigms are still in their infancy and require further rigorous exploration across virtually every domain.</p>