CASP14 (caspase-14) is a non-apoptotic cysteine protease with specialized functions in epidermal differentiation and cornification. It is the predominant caspase in the stratum corneum 1 and plays a critical role in keratinocyte maturation by proteolytically processing filaggrin and other substrates containing the [WY]-X-X-D motif 23. CASP14 mediates DNA fragmentation in differentiated keratinocytes through cleavage of DFFA/ICAD, releasing the nuclease DFFB/CAD 4. Beyond skin, it may contribute to retinal pigment epithelium barrier function 5. Genetically, CASP14 is regulated transcriptionally and post-transcriptionally by phosphorylated ΔNp63α via microRNA modulation in squamous cell carcinoma cells 6. CASP14 genetic polymorphisms (rs8110862) are associated with childhood leukemia risk, suggesting roles in apoptosis regulation beyond differentiation 7. CASP14 polymorphisms also correlate with skin barrier function and susceptibility to chemical-induced skin immunotoxicity 8. Mutations in CASP14 cause autosomal recessive congenital ichthyosis type 12, demonstrating its essential role in maintaining epidermal homeostasis and barrier integrity.