Current interest in photodynamic therapy (PDT) in dermatology stems from its recognized success in dermatological oncology, straightforward approach, easy accessibility and low cost. PDT is a photochemistry-based modality in which a light-activated photosensitizer (PS) destroys tissue through oxygen-dependent and -independent mechanisms. Although PDT has been used in dermatology for several decades, its application has still not extended significantly into the routine management of neoplastic and proliferative dermatoses because of continuing issues with the selectivity of the PS for affected tissues. This review analyzes prospects for optimization of PDT for the management of dermatoses with defects in keratinocyte proliferation/differentiation, and discusses the use of differentiating agents that redirect metabolic utilization within cells and lead to high levels of PS accumulation.