The clinical manifestations of drug eruptions can range from mild maculopapular 
exanthema to severe cutaneous adverse drug reactions (SCAR), including 
drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and 
systemic symptoms, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis 
(TEN) which are rare but occasionally fatal. Some pathogens may induce skin 
reactions mimicking SCAR. There are several models to explain the interaction of 
human leukocyte antigen (HLA), drug and T-cell receptor (TCR): (i) the 
"hapten/prohapten" theory; (ii) the "p-i concept"; (iii) the "altered peptide 
repertoire"; and (iv) the "altered TCR repertoire". The checkpoints of molecular 
mechanisms of SCAR include specific drug antigens interacting with the specific 
HLA loci (e.g. HLA-B*15:02 for carbamazepine-induced SJS/TEN and HLA-B*58:01 for 
allopurinol-induced SCAR), involvement of specific TCR, induction of 
T-cell-mediated responses (e.g. granulysin, Fas ligand, perforin/granzyme B and 
T-helper 1/2-associated cytokines) and cell death mechanism (e.g. 
miR-18a-5p-induced apoptosis; annexin A1 and formyl peptide receptor 1-induced 
necroptosis in keratinocytes). In addition to immune mechanism, metabolism has 
been found to play a role in the pathogenesis of SCAR, such as recent findings 
of strong association of CYP2C9*3 with phenytoin-induced SCAR and impaired renal 
function with allopurinol SCAR. With a better understanding of the mechanisms, 
effective therapeutics and prevention for SCAR can be improved.