Signifcant sex and gender diferences exist in cancer mechanisms, incidence, and survival, yet it is difcult to translate these important diferences because cancer phenotypes do not segregate into dichotomous male versus female or man versus woman categories. Instead, sex and gender are developmental and environmental forces that work together to establish the exquisite diversity of human phenotypes from imprints to death. Sex and gender efects are entangled in human phenotypes, which means that sex- or gender-specifc cancer treatments are unrealistic. The translational goal of cancer research should be to establish the efects of gender-sex entanglement (GSE) on cancer protection at the cellular, tissue, and systems levels. This will be essential for the adaptation of therapy to the varying efects of GSE on cancer phenotypes. To take a step in this direction, this chapter examines similarities in 8,370 transcriptomes of 26 diferent adult and 4 diferent pediatric cancers. Individual transcriptomic phenotype is assumed to be a product of GSE, and each patient’s transcriptome was allowed to cluster by similarity into naturally occurring local clusters that refected XX or XY characteristics. A transcriptomic index (TI, ranging from 0 to 1) was then calculated using a metric based on the local enrichment of male- or female-specifc characteristics, which was subsequently used to identify reference poles. Using TI values, patient-specifc GSE efects on targetable pathways (e.g., cell cycle signaling and immunity) are described.