Pyoderma gangrenosum (PG) is a rare neutrophilic inflammatory skin disease, characterized by recurrent skin ulcers, which in almost 50% of cases are associated with systemic autoimmune disorders, including rheumatoid arthritis, chronic hepatitis, inflammatory bowel disease, paraproteinemias and hematological malignancies. A systematic search of literature for PG was carried out using the PubMed, Embase, and Google Scholar databases for the purpose of this review and 2780 articles were retrieved up to February 2017. Inflammation represents the predominant aspect of the disease, but its pathophysiological mechanisms are not completely clear yet, since there are many studies showing only one or more isolated findings of the disease. The goal of PG treatment is to reduce inflammation in order to promote ulcer healing by minimizing side effects of therapy. Several systemic and local treatments are available, but the lack of large randomized double-blind studies results in an absence of a uniform therapeutic standard: thus, more clinical studies are required in order to make head-to-head comparisons between combination and single-drug therapies and to identify specific combination therapies for distinctive clinical patterns of PG.