Sulfur containing amino acids contribute substantially to the maintenance and integrity of cellular systems by influencing cellular redox state and cellular capacity to detoxify toxic compounds, free radicals and reactive oxygen species. Methionine and cysteine are the two primary sulfur-containing amino acids in mammals. Methionine is an essential amino acid, obtained by dietary intake while cysteine is non-essential and a metabolite of methionine metabolism. Each of these amino acids contributes significantly to the cellular pool of organic sulfur and generally to sulfur homeostasis as well as playing a significant role in regulation of one carbon metabolism. Genetic defects in the enzymes regulating sulfur pools produce a variety of human pathologies, including homo- and cystinuria, homo- and cysteinemia, and neural tube defects. In addition, thiol imbalance has been associated with multiple disorders, including vascular disease, Alzheimer's, HIV and cancer. Possible treatments to restore the thiol balance are also discussed.