HUMAN chorionic gonadotropin (hCG) is a glycoprotein hormone normally secreted by trophoblastic cells of the placenta during pregnancy. Trophoblastic tumors and some nontrophoblastic tumors also secrete hCG and/or its α- or β-subunit. This review emphasizes a number of aspects, some controversial, of hCG biosynthesis and secretion that have received intense investigation in recent years. Many of the studies have utilized hCG-secreting malignant cell lines derived from trophoblastic and nontrophoblastic tumors. The prohormone mechanism for hCG biosynthesis has lost favor in light of recent molecular biological studies which demonstrate that the α- and β-subunits are synthesized separately. The nascent α- and β-subunits of hCG are glycosylated by en bloc attachment of high-mannose complex-type oligosaccharides to two asparagine residues of each subunit. After excess mannose and glucose residues are trimmed from the intermediates, peripheral monosaccharides (N-acetylglucosamine, galactose, N-acetylneuraminic acid) are attached sequentially to complete the oligosaccharide structures. The α- and β-subunits combine in a two-step reaction. Morphological and biochemical evidence suggest that the plasma membrane may play a major role in hCG secretion, in contrast to the pathway involving exocytosis and secretory granules that operates in other endocrine tissues. In trophoblastic tissues, hCG synthesis and secretion are stimulated by dibutyryl cyclic AMP and by inhibitors of DNA synthesis, perhaps by different mechanisms. Dibutyryl cyclic AMP has a significantly lesser stimulatory effect on hCGsecreting nontrophoblastic cell lines, many of which are preferentially stimulated by butyrate instead. It is possible that trophoblastic hCG secretion may be regulated differently than nontrophoblastic hCG secretion. A placental gonadotropin releasing factor (possibly mediated by cyclic AMP) may be the primary physiological stimulus for placental hCG secretion, although results to date are still inconclusive. The production of hCG-like substances by normal tissues may represent derepression phenomena or eutopic hormone secretion by undifferentiated stem cells. Some bacteria also produce an hCGlike substance, perhaps as a consequence of in vivo DNA recombination. In some cases, the apparent hCG-like activity is a result of serine protease activity. Future trends in research on hCG biosynthesis are also discussed.