Cell growth and division require the biosynthesis of macromolecule components and cofactors (e.g., nucleotides, lipids, amino acids, and nicotinamide adenine dinucleotide phosphate [NADPH]). Normally, macromolecular biosynthesis is under tight regulatory control, yet these anabolic pathways are often dysregulated in cancer. The resulting metabolic reprogramming of cancer cells is thought to support their high rates of growth and division. The mechanisms that underlie the metabolic changes in cancer are at least partially understood, providing a rationale for their targeting with known or novel therapeutics. This review is focused on how cells sense and respond transcriptionally to essential nutrients, including glucose and glutamine, and how MAX- and MLX-centered transcription networks contribute to metabolic homeostasis in normal and neoplastic cells.