The current study employs the latest data-independent acquisition mass spectrometry (DIA-MS) technique to investigate the molecular changes in formalin-fixed and paraffin-embedded (FFPE) samples of lymph node and distant organ metastatic melanomas compared to the primary lesions to complement previous findings while identifying novel proteomic and molecular changes happening during the melanogenic journey. The findings from this study will provide up-to-date information about molecular information about how primary melanomas may progress to regional and distant organ body sites and will guide the development of novel therapeutic targets, leading to improved patients' response and survival.