The optimal treatment of pyoderma gangrenosum includes a combination of local wound care and systemic medications. Oral and pulse intravenous corticosteroids have traditionally been the most commonly recommended first-line systemic therapies. Cyclosporine, with or without corticosteroids, has more recently emerged as a first-line systemic treatment. A multitude of immunosuppressive and immune-modulating medications, as well as antimicrobial agents with anti-inflammatory properties have also been widely prescribed. Often, it is difficult to achieve control of aggressive cases of pyoderma gangrenosum, necessitating administration of a combination of systemic therapies. Furthermore, patients recalcitrant to one or many medications are frequently reported. Concomitant disease, intolerance to a class of medications, and the patient's response to prior therapies can help guide a practitioner in choosing the optimal treatment of pyoderma gangrenosum.