Indirect pathways, involving homocysteine (Hcy)-thiolactone and S-nitroso-Hcy, allow incorporation of Hcy into protein. Hcy-thiolactone, synthesized by methionyl-tRNA synthetase in all organisms investigated, including human, modifies proteins post-translationally by forming adducts in which Hcy is linked by amide bonds to epsilon-amino group of protein lysine residues. S-Nitroso-Hcy, synthesized in human vascular endothelial cells, is incorporated translationally into peptide bonds in protein at positions normally occupied by methionine. Hcy-N-hemoglobin and Hcy-N-albumin constitute a major pool of Hcy in human blood. Hcy-thiolactone is present in human plasma. Modification with Hcy-thiolactone leads to protein damage. Hcy-thiolactone is detoxified by Hcy-thiolactonase/paraoxonase present in a subset of high-density lipoprotein particles in humans.