Refractory angina is a debilitating disease with limited therapeutic options that is primarily caused by microvascular dysfunction and desertification. Toward addressing this unmet need, microvascular revascularization therapy has progressively evolved from the lizard heart-inspired transmyocardial revascularization to precisely inducing vascular endothelial growth factor with gene therapy. Gene therapy with adenoviral vehicles or naked modified ribonucleic acid is safe and shows early signs of clinical promise but has not yet been proven effective due to gaps in optimization.