Serine hydroxymethyltransferase (SHMT) is also called as serine aldolase. It is a pyridoxal-phosphate (PLP) dependent enzyme that plays a central role in the onecarbon metabolism. It catalyzes the reversible inter-conversion of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate, a key intermediate in the biosynthesis of purine, thymidine, choline, and methionine. In addition to this physiological reaction, SHMT has also been shown to catalyze THF-independent aldolytic cleavage, decarboxylation, racemization, and transamination reactions. The PLP dependent enzymes can be classified based on structure and sequence analysis into five major groups of different evolutionary origin: aspartate aminotransferase superfamily (fold type I), tryptophan synthase beta superfamily (fold type II), alanine racemase superfamily (fold type III), D-amino acid superfamily (fold type IV) and glycogen phophorylase family (fold type V). Both eukaryotic and prokaryotic SHMT enzymes form tight obligate homodimers and the mammalian enzyme forms a homotetramer. The importance of SHMT in DNA synthesis together with the high level of enzyme activity in rapidly proliferating cells has focused attention on SHMT as a potential drug target.