This Reprint presents an integrated and contemporary overview of natural photosensitizers and their applications in photodynamic therapy. It brings together experimental, mechanistic, and translational studies that demonstrate how plant-derived and microbial chromophores can be harnessed to produce cytotoxic, antimicrobial, and immunomodulatory effects upon controlled light activation. This Reprint highlights advances in molecular photobiology, photophysical characterization, and cellular responses, as well as innovations in nanoformulations that improve solubility, stability, and therapeutic selectivity. Particular attention is given to antimicrobial resistance, oncologic applications, and neglected diseases in which photodynamic therapy offers accessible and minimally invasive alternatives. By combining fundamental science with clinically relevant perspectives, this Reprint provides a comprehensive synthesis of current progress and emerging directions in the development of natural photosensitizers for modern photodynamic therapy.