Hydroxylation is an emerging modification generally catalyzed by a family of ∼70 enzymes that are dependent on oxygen, Fe(II), ascorbate, and the Kreb's cycle intermediate 2-oxoglutarate (2OG). These "2OG oxygenases" sit at the intersection of nutrient availability and metabolism where they have the potential to regulate gene expression and growth in response to changes in co-factor abundance. Characterized 2OG oxygenases regulate fundamental cellular processes by catalyzing the hydroxylation or demethylation (via hydroxylation) of DNA, RNA, or protein. As such they have been implicated in various syndromes and diseases, but particularly cancer. In this review we discuss the emerging role of 2OG oxygenases in gene expression control, examine the regulation of these unique enzymes by nutrient availability and metabolic intermediates, and describe these properties in relation to the expanding role of these enzymes in cancer.