Utilization of unique acidic environment in various disease sites has been quite advantageous in targeted drug delivery. Among the widely explored pH-sensitive moieties such as hydrazone, orthoester, imine, vinylether, etc., the acetal bearing compounds are one of the most explored entities in targeted and improved drug delivery to treat disease conditions at the preclinical stage. This review addresses the design and synthesis of various acetalbased polymers as pH-responsive nano-drug delivery systems in the form of micelles, polymersomes, nanoplexes and polymeric and solid lipid nanoparticles for biomedical applications. The review will identify potential advantages, key challenges and future prospects of acetal-based pH-responsive drug delivery systems. The novel developments, strategies and suggestions described may guide the formulation scientists to optimize acetalbased pH-responsive drug delivery systems as an approach to treat various diseases.