Site-specific drug delivery is among the main objectives for the optimization of pharmaceutical therapies. In particular, local drug delivery systems represent a way to avoid systemic administration, reducing the associated side effects and increasing patient compliance. In the design of local drug delivery systems, different strategies to overcome physiological barriers to obtain effective drug concentration at the target site without affecting adjacent tissues can be pursued. Physical and chemical enhancers, microneedles, and nanostructured drug delivery systems have been proposed as effective tools to influence drug release and partition in the target tissues. Innovative drug delivery systems could be based on natural or synthetic polymers that are biodegradable, endowed with stimuli-responsive behavior, and, if applicable, mucoadhesive properties.