The serine glycine and one-carbon pathway (SGOCP) is a crucially important metabolic network for tumorigenesis, of unanticipated complexity, and with implications in the clinic. Solving how this network is regulated is key to understanding the underlying mechanisms of tumor heterogeneity and therapy resistance. Here, we review its role in cancer by focusing on key enzymes with tumor-promoting functions and important products of the SGOCP that are of physiological relevance for tumorigenesis. We discuss the regulatory mechanisms that coordinate the metabolic flux through the SGOCP and their deregulation, as well as how the actions of this metabolic network affect other cells in the tumor microenvironment, including endothelial and immune cells.