The development and maturation of protease-cleavable linkers as an efficient and flexible linker strategy, compatible with a variety of payload classes, is described. Lysosomal proteases such as cathepsins and legumain have been employed successfully to release active payloads from antibody–drug conjugates (ADCs) with peptide linkers composed of appropriate substrate sequences for respective cleavage enzymes and on demand, with additional self-immolative spacer fragments. Case studies of approved ADCs are reviewed, along with further improvements of linker stability, cleavage specificity, and reduced tendency for aggregate formation. Initial investigations to expand the scope to extracellular payload release from non-internalizing ADCs by proteases in the tumor microenvironment such as cathepsin B and matrix metalloproteinases complete the overview.