Erroneous activation of the pain-sensing system, as in chronic or neuropathic 
pain, represents a major health burden with insufficient treatment options. 
However, the study of genetic disorders rendering individuals completely unable 
to feel pain offers hope. All causes of congenital painlessness affect 
nociceptors, evolutionarily conserved specialist neurons able to sense all type 
of tissue damage. The discovery of new genes essential for sensing pain (SCN11A, 
PRDM12, and CLTCL1) has provided unexpected insights into the biological 
mechanisms that drive distinct stages of nociception. Drugs targeting two 
previously discovered painlessness genes, NGF and SCN9A, are currently in 
late-stage clinical trials; thus, characterization of these new painlessness 
genes has significant potential for the generation of new classes of analgesics.