The transcription factor NRF2 (encoded by the gene Nuclear Factor, Erythroid 2 Like 2 [NFE2L2]) is a master regulator of the transcriptional response to oxidative stress. In the presence of excess reactive oxygen species, NRF2 induces expression of antioxidant genes via its interaction with regulatory DNA sequences known as antioxidant response elements (AREs). However, oxidative stress is not the only context in which NRF2 can be activated. Somatic mutations that disrupt the interaction between NRF2 and KEAP1, an important inhibitor of NRF2, lead to NRF2 hyperactivation and promote tumorigenesis. The exact mechanisms underlying NRF2’s oncogenic properties remain unclear, but likely involve aberrant expression of select NRF2 target genes. We tested this possibility using an integrative genomics approach, combining our own NRF2-centric functional genomics data with thousands of tumor genome and transciptome profiles from The Cancer Genome Atlas (TCGA), to get a precise view of the direct NRF2 target genes dysregulated in tumors with NRF2 hyperactivating mutations. This approach revealed a core set of 32 direct NRF2 targets that are consistently upregulated in NRF2 hyperactivated tumors. This set of NRF2 “cancer target genes” includes canonical redox-related NRF2 targets (NQO1, TRX, GCLC, etc.), as well as several target genes that have not been previously linked to NRF2 activation; NRF2-driven upregulation of this gene set is largely independent of the organ system where the tumor developed. This critical subset of NRF2 targets is significantly enriched for genes functionally linked to oncogenesis, and several features differentiate these genes from other NRF2 targets. One of the key distinguishing features is that the NRF2 cancer target genes are regulated by high affinity, switch-like AREs that fall within genomic regions that possess a distinct, ubiquitously permissive chromatin signature. This finding implies that the NRF2 cancer target genes are highly responsive to oncogenic NRF2 in most tissues because the AREs at these loci lack the epigenetic constraints that restrict expression of most other NRF2 targets genes. Notably, the NRF2 cancer target gene set also serves as a reliable proxy for NRF2 activity. Identification of tumors with hyperactive NRF2 is difficult because there are many routes to its activation – mutations in NRF2, KEAP1, or CUL3; epigenetic silencing of KEAP1; etc. – so we used this 32 gene set to infer NRF2 activity based on RNA-seq data from thousands of tumors profiled by the TCGA project. This approach revealed that high NRF2 activity is associated with significant decreases in survival in at least 10 different cancers, including liver hepatocellular carcinoma, papillary kidney carcinoma, urothelial bladder cancer, and head and neck squamous cell carcinoma. Overall, the pervasive upregulation of these NRF2 cancer targets across multiple cancers, and their association with negative prognostic outcomes, suggest that these genes will be central to dissecting the functional implications of NRF2 hyperactivation in several cancer contexts.