Gene delivery systems can be divided into two main categories: viral systems and nonviral systems. Nonviral vectors are immunologically inert, easily constructible plasmid-based systems including liposomes, microbubble-enhanced ultrasound, synthetic polymers, gene guns, naked DNA, nucleofection, and DNA–ligand complexes. Gene therapy consists in the transfer of exogenous genetic material into the genome of target cells so as to modulate gene expression by enhancing the synthesis of beneficial and/or missing proteins or by inhibiting the synthesis of detrimental products. Viral cytotoxicity and mutagenicity are among the main risks associated with gene therapy: this has led to the development of safer viral vectors, most notably Adeno-associated virus, as well as engineered nonviral vectors. Several and diverse molecules and growth factors have been targeted, using either different viral vectors, nonviral vectors, or RNAi, all yielding promising and significant results in terms of intervertebral disc structure preservation, increased matrix anabolism, and reduced cell loss.