Michael Cashel was born in Worthington, MN (1937), BA in biology/chemistry at Amherst College working on radiological target size of Salmonella typhimurium phage 22 transduction, then M.D. in 1963 at CRU School of Medicine working with Dr. Frederick Robbins on tissue culture genetics followed by studies in USPHS of Bacillus subtilis sporulation and DNA crosslinking with Dr. Ernst Freese at NIH. Then on a USPHS training grant I went to the University of Washington and received a Ph.D. in Genetics with Dr. Jonathan Gallant in 1968. In the course of this work discovered a spot on thin layer chromatograms that appeared during the operation of E.coli stringent response to amino acid starvation. I returned to NIH in 1967 to work out the composition of material, which turned out to be nucleotide analogs of GDP and GTP with the ribosyl 3' hydroxyl derivatized with pyrophosphates [(p)ppGpp]. Subsequent studies led to understanding the molecular basis of their regulation of these nucleotides as generalized sensors of stress and subtle perturbations of carbon and amino acid biosynthesis metabolism which function to curtail cellular activities that are superfluous during times of stress including nutritional deficiency. These signals accomplish this through global effects on gene expression at the level of direct interactions with the RNA transcriptional apparatus rather than processes mediated by DNA recognition proteins, as is the case for classical nucleotide second messengers such as cAMP. The ability to respond to the stress of environmental changes is common to all cells in biology whereas the (p)ppGpp regulatory nucleotides are currently known to have similar regulatory functions in bacteria and plants. Currently there are hints that that this regulatory system may extend to animals in a modified form, which are currently being pursued.