The therapeutic landscape for melanoma evolved drastically in the past decade. Currently, immune checkpoint inhibitors and small molecule inhibitors targeting the MAPK pathway are the two mainstay therapies for BRAF V600 mutant advanced melanoma. Although MAPK dependence has been variably demonstrated in melanomas lacking BRAF V600 mutations, definitive evidence of benefit with MAPK inhibitors has not been demonstrated. Thus, in the BRAF V600 “wild-type” setting, immune checkpoint inhibitors are the standalone option(s). In the BRAF V600 mutant setting, there is no definitive evidence prioritizing one therapeutic modality over another. Herein we review the updated data of the pivotal phase III randomized control trials that established the standard-of-care first line treatment for advanced melanoma, as it provides insights regarding long-term benefit which is a primary motivator of therapy selection. We discuss clinical considerations for choosing amongst these therapies in the front-line setting and beyond, specifically for BRAF V600 mutant patients based on currently available evidence. We have previously proposed a time-dependent resistance paradigm in which future therapeutic development strategies can be rooted. We also discuss how these FDA-approved therapeutic modalities are being pursued earlier in the course of disease management, namely in adjuvant and neoadjuvant settings. FDA approved interlesional oncolytic virotherapy in the modern era is also briefly discussed.This article is protected by copyright. All rights reserved.