Drug delivery vectors have the potential to improve the efficacy of therapeutics, including small molecules and nucleic acidbased drugs. However, challenges remain in developing linkages that enable the precise and efficient release of therapeutic cargo in response to mildly acidic environments or lysosomal enzymes. This review highlights recent advances in acid-degradable acetal/ketal and enzyme-cleavable linkages for endolysosomal release. These innovations include the developments of azido-acetal linkers with improved stability and synthesizing asymmetric ketals and their applications in drug delivery, and enzyme-cleavable linkers activated by cathepsin B or b-galactosidase.