Good oral health is of major importance for general health and well-being. Several innovative drug delivery systems have been developed for the local treatment and prevention of various diseases in the oral cavity. However, there are currently few optimal systems and many therapeutic challenges still remain, including low drug efficacy and retention at targeted site of action. The present review provides an insight into the latest drug delivery strategies for the local treatment and prevention of the four most common oral pathologies, namely, dental caries, periodontitis, oral mucosal infections and oral cancer. The potential of bioadhesive formulations, nanoparticulate platforms, multifunctional systems and photodynamic methodologies to improve therapy and prophylaxis in future local applications for the oral cavity will be discussed.