The autonomic nervous system exerts a fine beat-to-beat regulation of cardiovascular functions and is consequently involved in the onset and progression of many cardiovascular diseases (CVDs). Selective neuromodulation of the brain-heart axis with advanced neurotechnologies is an emerging approach to corroborate CVDs treatment when classical pharmacological agents show limited effectiveness. The vagus nerve is a major component of the cardiac neuroaxis, and vagus nerve stimulation (VNS) is a promising application to restore autonomic function under various pathological conditions. VNS has led to encouraging results in animal models of CVDs, but its translation to clinical practice has not been equally successful, calling for more investigation to optimize this technique. Herein we reviewed the state of the art of VNS for CVDs and discuss avenues for therapeutic optimization. Firstly, we provided a succinct description of cardiac vagal innervation anatomy and physiology and principles of VNS. Then, we examined the main clinical applications of VNS in CVDs and the related open challenges. Finally, we presented preclinical studies that aim at overcoming VNS limitations through optimization of anatomical targets, development of novel neural interface technologies, and design of efficient VNS closed-loop protocols.