Hypoxia is a common feature in various solid tumors including melanoma. 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 cancer cell survival in hypoxic environments can reveal potential vulnerabilities that can be exploited to improve efficacy of anti-cancer therapies. We carried out temporal proteomic and phosphoproteomic profiling in melanoma cell lines to identify hypoxia induced protein expression and phosphorylation changes. By employing TMT based quantitative proteomics strategy, we identified and quantified >7,000 proteins and >10,000 phosphosites in melanoma cell lines grown in hypoxia. Proteomic data showed metabolic reprogramming as one of the prominent adaptive responses in hypoxia. We identified several novel hypoxia mediated phosphorylation changes that have not been reported before. They reveal kinase-signaling pathways that are potentially involved in modulating cellular response to hypoxia. In addition to known protein expression changes, we identified several novel proteomic alterations associated with adaptive response to hypoxia. We show that cancer cells are dependent on ubiquitin-proteasome system to survive in hypoxia. Inhibition of proteasome activity affects cell survival and may provide a novel therapeutic avenue to target cancer cells in hypoxia. Our study can serve as a valuable resource to pursue several novel candidates to target hypoxia in cancers and improve efficacy of anticancer therapies.