This chapter describes the main deregulated intracellular pathways at both genetic and proteomic levels that are found in three main skin cancers: basal cell carcinoma, squamous cell carcinoma and melanoma. In basal cell carcinoma, the main intracellular signaling pathways is the Sonic Hedgehog pathway, while in squamous cell carcinoma, it is the p53 pathway. However, in both nonmelanoma skin cancers, these major pathways trigger cross-activation with other important ones. In melanoma, mitogen-activated protein kinase pathway and PI3K/Akt pathways are deeply deregulated, and moreover due to the disease complexity, BRAF, RAS (N/H/K), NF1 and Triple-WT melanoma subtypes need additional molecular stratification. The stage in which photodynamic therapies' clinical application is in the treatment of these diseases is another subject tackled by the chapter. Thus, if basal cell carcinoma and squamous cell carcinoma possess in their therapeutical armamentarium photodynamic therapies approach, melanoma, with its particularities, still needs thorough molecular investigations to adapt this particular therapy. Based on the accumulated knowledge on pathological intracellular pathways, the chapter describes the molecular details that reside in applying photodynamic therapy. In vivo and in vitro models of cutaneous malignancy and photodynamic therapies' molecular events are further detailed.