Health problems and reduced treatment effectiveness due to antimicrobial resistance have become important global problems and are important factors that negatively affect life expectancy. Antimicrobial photodynamic therapy (APDT) is constantly evolving and can minimize this antimicrobial resistance problem. Reactive oxygen species produced when nontoxic photosensitizers are exposed to light are the main functional components of APDT responsible for microbial destruction; therefore, APDT has a broad spectrum of target pathogens, such as bacteria, fungi, and viruses. Various photosensitizers, including natural extracts, compounds, and their synthetic derivatives, are being investigated. The main limitations, such as weak antimicrobial activity against Gram-negative bacteria, solubility, specificity, and cost, encourage the exploration of new photosensitizer candidates. Many additional methods, such as cell surface engineering, cotreatment with membrane-damaging agents, nanotechnology, computational simulation, and sonodynamic therapy, are also being investigated to develop novel APDT methods with improved properties. In this review, we summarize APDT research, focusing on natural photosensitizers used in in vitro and in vivo experimental models. In addition, we describe the limitations observed for natural photosensitizers and the methods developed to counter those limitations with emerging technologies.