Several phase I/II clinical trials are currently ongoing in gene therapy of cardiovascular disease. Whereas the indications vary, including peripheral artery disease, ischemic heart disease, post-angioplasty restenosis, and vein graft failure, these trials are mostly based on the use of adenoviral vectors and nonviral vectors. Novel vectors aimed at improving the efficacy and safety of gene delivery in target organs, such as heart, skeletal muscle, vasculature, and liver, have been recently generated. Some of them have already been successfully validated in preclinical models of cardiovascular disease. This review focuses on the most recent advances in vector development that could substantially increase the spectrum of cardiovascular pathologies amenable to gene transfer-based treatments.