First-generation AAV gene therapies generally transduce a minority of target cells and may thus have limited efficacy. Cross correction strategies offer a solution to this problem by turning transduced cells into therapeutic protein “factories” that deliver transgene product to both themselves and more broadly to their untransduced neighbors. Multiple engineering strategies can enhance cross correction, with several preclinical programs demonstrating marked efficacy improvements in animal models. Cross correction strategies are furthest along in preclinical development for secreted lysosomal hydrolases, which can be delivered by endogenous surface receptors. Cytosolic proteins, transmembrane proteins, and mitochondrial proteins are more challenging targets, but new developments in cell-penetrating peptides, exosomal targeting, and tunneling nanotubes are opening the door for cross correcting a wide-variety of intracellular locales. Thus, while wild type gene therapies will enter the clinic first as important treatments, new cross correction strategies may greatly enhance therapeutic efficacy in subsequent next-generation therapies.