Photodynamic therapy (PDT) was discovered over 100 years ago when it was observed that certain dyes could kill microorganisms when exposed to light in the presence of oxygen. Since those early days, PDT has mainly been developed as a cancer therapy with regulatory approvals and clinical trials steadily accumulating for different types of cancer and different photosensitizer structures. A very important milestone for PDT was the introduction of 5-aminolevulinic acid (ALA), which functions as a prodrug to induce endogenous porphyrin biosynthesis that acts as an endogenous photosensitizer produced by our cells. PDT with ALA and its derivatives have become mainstays of the clinical dermatologist???s practice covering everything from skin cancer, premalignant lesions, acne, and skin rejuvenation. Another milestone in PDT development was the realization that PDT may also be used as an effective antimicrobial modality and a potential treatment for localized infections. To some extent, this means that PDT has gone full circle and returned to its roots from when it was first discovered in 1900. In this chapter we discuss, in a contextualized fashion, what are the expected characteristics of an ideal photosensitizer and which are the main molecular frameworks used for development of synthetic, natural, and nanostructured photosensitizers.