The metabolism of sulfur (S) compounds concurs to the maintain of cell homeostasis and tissue integrity in the human body. Sulfur chemical species act in all cells as anti-oxidant/scavenging agents or regulators of membrane stability/excitability. At the same time, they also exert tissue-dependent functions behaving as protective molecules of the liver and cardiovascular system, as modulators of the immune response, gut activity and CNS neurotransmitter signaling. The involvement of S compounds in human complex, chronic, disabling diseases at multifaceted pathogenesis is actually under investigation: altered levels of S metabolites could be in fact bio-indicators of impaired oxidation state in the body and their unbalance could be risk factors for disease onset. By the present review, we will discuss data from the literature which unearth an altered S biochemistry in human complex illnesses, taking as an example highly invalidating neuropsychiatry and pain perception diseases as autism spectrum disorders (ASD), schizophrenia and fibromyalgia. As well, we will depict herein the utility at applying to this area of the clinical research high resolving -omics strategies in combination with methodological tools which specifically explore S metabolism in patients. The perspectives of these kind of analyses would be the adoption of more valuable, personalized therapeutics protocols and, possibly, an improved bio-monitoring of patients, also including their response to treatments.