Simple Summary: Many novel therapeutic options have emerged in recent years for patients with locoregionally advanced and metastatic melanoma. For in-transit melanoma with metastatic tumor spread between the primary tumor site and the regional lymph node basin, treatment options include intralesional tumor injections and an isolated infusion of the affected extremity. Notably, for ocular melanoma with metastatic disease to the liver, recent FDA approval of percutaneous hepatic perfusion, a minimally invasive method of isolated infusion of the liver, has become an approved treatment option. This article aims to review the current updates and efficacy on intralesional and infusional therapies for locoregionally advanced and metastatic melanoma. Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of advanced melanoma, followed by the utilization of isolated extremity perfusion (ILP). Following this, intralesional oncolytic viruses, xanthene dyes, and cytokines were introduced for the management of in-transit metastases as well as unresectable, advanced melanoma. In 2015, the Food and Drug Administration (FDA) approved the first oncolytic intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of advanced melanoma. Additionally, immune checkpoint inhibition has demonstrated efficacy in the management of advanced melanomas, and this improvement in outcomes has been extrapolated to aid in the management of in-transit metastatic disease. Finally, percutaneous hepatic perfusion (PHP), also approved by the FDA, has been reported to have a significant impact on the treatment of hepatic disease in uveal melanoma. While some of these treatments have less utility due to inferior outcomes as well as higher toxicity profiles, there are selective patient profiles for which these therapies carry a role. This review highlights intralesional and infusional therapies for the management of metastatic melanoma. [ABSTRACT FROM AUTHOR]