The interconversion of metabolites provides the bases of the exchange of materials between organisms and their surroundings, and the connections among different physiologies. We found that metabolites are sensed through different mechanisms and deregulated metabolites-sensing contribute to pathology of various diseases. Acetyl-CoA, an indicator of both energy and nutrients, is sensed by protein lysine acetylation that regulates homeostasis of metabolites including glucose. α-Ketoglutarate is sensed by α-Ketoglutarate-dependent dioxygenases family proteins. IDH1 mutations produced 2-hydroxyglutarate or FH and SDH mutations accumulated fumarate and succinate promotes tumorigenesis through either disrupting α-Ketoglutarate sensing that alters epigenetics or promoting hypersuccinylation that induces cancerous metabolism and apoptosis resistance. Amino acids are sensed by tRNA synthetases and their signals are transmitted via lysine aminoacylation. The revealing of metabolites sensing and signal transmitting mechanisms is providing us opportunities to identify novel drugable targets.