The signaling networks that mediate cell growth, differentiation, and survival are dependent on complex metabolic and redox pathways. Metabolism of glucose through the pentose phosphate pathway (PPP) fulfills two unique functions: formation of ribose 5‐phosphate for the synthesis of nucleotides, RNA, and DNA in support cell growth and formation of NADPH for biosynthetic reactions and neutralization of reactive oxygen intermediates (ROI). Balancing of NADPH and ROI levels by the PPP enzyme transaldolase (TAL) regulates the mitochondrial trans‐membrane potential (Δψm), a critical checkpoint of ATP synthesis and cell survival. While complete deficiency of glucose 6‐phosphate dehydrogenase (G6PD) or transketolase (TK) is lethal, TAL‐deficient mice developed normally with the exception of male sterility due to structural and functional damage of sperm cell mitochondria. Recently, two cases of complete TAL deficiency have been reported in patients with liver cirrhosis which results from increased cell death of hepatocytes. Delineation of the cell type‐specific role that TAL plays in the PPP and cell death signal processing will be critical for understanding the pathogenesis of TAL deficiency. iubmb Life, 59: 1‐9, 2007