Hypoxia and HIF1α signaling direct tissue‐specific gene responses regulating tumor progression, invasion, and metastasis. By integrating HIF1α knockdown and hypoxia‐induced gene expression changes, this study identifies a melanocyte‐specific, HIF1α‐dependent/hypoxia‐responsive gene expression signature. Integration of these gene expression changes with HIF1α ChIP‐Seq analysis identifies 81 HIF1α direct target genes in melanocytes. The expression levels for 10 of the HIF1α direct targets – GAPDH, PKM, PPAT, DARS, DTWD1, SEH1L, ZNF292, RLF, AGTRAP, and GPC6 – are significantly correlated with reduced time of disease‐free status in melanoma by logistic regression (P‐value = 0.0013) and ROC curve analysis (AUC = 0.826, P‐value < 0.0001). This HIF1α‐regulated profile defines a melanocyte‐specific response under hypoxia, and demonstrates the role of HIF1α as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization, and invasion.