Photodynamic therapy (PDT) with methylaminolevulinate (MAL) has demonstrated high efficacy, minimal side effects, and improved cosmetic outcome in the treatment of its EU-approved clinical indications, i.e. actinic keratoses (AKs), basal cell carcinoma, and Bowens disease. In addition, PDT with MAL or 5-aminolevulinic acid (ALA) is approved in the US for the treatment of AK. However, besides anti-tumoral activity, PDT has also demonstrated various anti-inflammatory and anti-infectious effects as well as those on the metabolism of connective tissue, keratinization of normal keratinocytes and maturation processes of sebaceous glands and hair follicles. These findings have expanded the spectrum of possible applications of PDT that now encompasses infectious (viral, bacterial, fungal, protozoal) disorders, epidermal and dermal inflammatory diseases, tumors of lymphocytes, adnexal diseases and premature skin aging due to sun exposure. However, the findings obtained so far must be considered in most off-label indications only preliminary and more detailed studies are required to clarify the role of PDT beyond the treatment of non-melanoma skin cancer. In addition, possible advantages over standard treatments remain to be clarified.