Porokeratosis is a genetically heterogeneous disorder with multiple loci identified to date; however, the pathogenetic mechanisms remain elusive. Loci at chromosome bands 12q23.2–24.1 and 15q25 (DSAP1 and DSAP2) have been reported in familial disseminated superficial actinic porokeratoses; a further locus has been identified for disseminated superficial porokeratosis (DSP) at 18p11.3.4,5 The locus at DSAP1 corresponds to a candidate gene, SART3 (squamous cell antigen recognized by T cells 3); this encodes a tumor rejection antigen thought to be involved in the regulation of messenger RNA splicing. Fine mapping of the locus at DSAP1 has also revealed mutations in another potential candidate gene, SSH1 (slingshot 1), and a variation in the promoter region of ARPC3, which play a key role in actin dynamics.6–8 Missense mutations in SSH1 in this kindred have been shown to result in loss of heterozygosity in DSAP.9 However, microarray expression and real time quantative polymerase chain reaction (PCR) profiles of SART3, SSH1, and ARPC3 have failed to show differential expression patterns.10,11 Porokeratosis punctata palmaris et plantaris maps to a 6.9-centimorgan region at chromosome band 12q24.1–24.2, overlapping with the region identified for DSAP1, suggesting that the two forms may be allelic.12 The centrifugal expansion of lesions is postulated to reflect the migration of a mutant clone of keratinocytes.13 Supporting this mutant clone theory are findings of abnormal DNA ploidy and chromosomal abnormalities in lesional keratinocytes.14 The tumor suppressor proteins p53 and pRb are overexpressed in keratinocytes immediately beneath and adjacent to the cornoid lamella, although to date p53 mutations have not been identified, and there is no significant expression of p53 at an mRNA level.15–19,11 Cytogenetic abnormalities in fibroblasts, particularly on chromosome 3, have also been documented.20,21 Decreased mdm2, abnormal expression of psi-3, cytokeratins, filaggrin, and involucrin have also been reported.22,23 The increased prevalence of porokeratosis in immunosuppressed patients suggests that impaired immunity may be permissive in genetically predisposed individuals.24–27 Other reported triggering factors such as exposure to ultraviolet (UV) light, together with the increased potential for malignant transformation, highlight the dysplastic potential of affected keratinocytes. Malignant degeneration has been described in all variants of porokeratosis, with the exception of the punctate variety.28–30