Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by ulcerating skin lesions with rapid onset and recalcitrant treatment course. PG treatment targets an array of inflammatory pathways with variable success. One of the hallmark features of PG is its association with a broad spectrum of systemic disorders. The authors hypothesize that there are common inflammatory pathways linking these systemic disorders to neutrophilic dermatoses. Rare autoinflammatory diseases offer insights into the understanding of inflammatory skin conditions. This article explores observations of the natural history of PG that illuminate aspects of PG pathogenesis, highlighting the role of autoinflammatory mediators.