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Granulomatous drug reactions have been associated with many medications, including targeted therapeutics such as biologics and small molecule inhibitors. The four main clinicopathologic reaction patterns are drug-induced sarcoidosis-like reaction, reactive granulomatous dermatitis, granuloma annulare, and accelerated rheumatoid nodulosis. These reactions often develop months after exposure to the causative medication and clinically can mimic other granulomatous diseases or metastatic cancer, which may be differentiated with biopsy, tissue culture, and radiographic imaging. Granulomatous inflammation may be limited to the skin, where early recognition helps to facilitate diagnosis. Cutaneous manifestations vary by reaction pattern, ranging from erythema nodosum-like lesions to painful rheumatoid nodules to annular indurated plaques. Systemic granulomatous inflammation is typically only observed in sarcoidosis-like reaction or accelerated rheumatoid nodulosis and most often involves the lungs or lymph nodes. Targeted therapeutics implicated in granulomatous drug reactions are TNFα inhibitors, BRAF and MEK inhibitors, immune checkpoint inhibitors and, to a lesser extent, other cytokine modulators. TNFα inhibitors, in particular, are among the most common drugs in any class associated with the four primary granulomatous drug eruptions. We review the current literature on granulomatous reactions to these agents, including proposed mechanisms and the range of clinical manifestations. Management may include drug discontinuation, topical therapy, or systemic immunosuppression depending on the severity of the granulomatous drug reaction. In the setting of malignancy, granulomatous inflammation does not appear to be of prognostic value, although more studies are needed.