Background Locoregional advanced melanoma poses a complex clinical challenge that requires a multidisciplinary, patient-centered approach. Numerous agents have been studied for their suitability as intralesional therapy in the past decades, but few have successfully completed phase 3 clinical trial testing. Methods The relevant medical literature was searched for articles regarding use of intralesional therapies in metastatic melanoma. Therapies with data from phase 2 or higher studies were selected for review. This review also summarizes the mechanisms of action, adverse-event profiles, and clinical data for these agents. Results Intralesional therapies demonstrate promising effects in select patients and are a valuable asset to the current treatment options in advanced melanoma. The optimal approach should be tailored to the individual patient and consists of a combination of intralesional therapies, regional perfusions, systemic immunotherapies, targeted therapies and/or surgery. Conclusions Due to relatively good local response rates and tolerable adverse-event profile, intralesional therapy may be a treatment option for patients with unresectable locally advanced or metastatic melanoma.