Hypoxia is a common feature in various solid tumors. Cancer cells in hypoxic environments are resistant to both chemotherapy and radiation. Hypoxia is also associated with immune suppression. Identification of proteins and pathways that regulate survival of cancer cells in hypoxic environments can reveal potential vulnerabilities that can be exploited to improve efficacy of anti-cancer therapy. Gene expression profiling studies have identified several hypoxia-induced genes. This includes well-known transcription factor hypoxia-inducible factor 1-alpha (HIF-1α). We carried out global proteome profiling and phosphoproteome profiling in melanoma cell lines to identify proteins and pathways that are induced by hypoxia. We used Orbitrap Fusion Mass Spectrometer for analysis and employed TMT-based quantitation for global proteomic and phosphoproteomic comparison. As expected, several proteins that are known targets of hypoxia inducible factors (HIFs) were found to be overexpressed in the hypoxic models. In addition, several metabolic enzymes showed altered expression revealing metabolic reprogramming in hypoxic conditions. Phosphoproteomic profiling revealed kinase mediated signaling pathways that are induced in hypoxic conditions. Our data provides a comprehensive view of proteomic alterations in hypoxic conditions and reveals potential mechanisms that regulate cell survival in hypoxic environments. These mechanisms can be targeted to improve therapeutic outcomes in cancer treatment.