The main role of insulin in the heart under physiological conditions is obviously the regulation of substrate utilization. Indeed, insulin promotes glucose uptake and its utilization via glycolysis. In addition, insulin participates in the regulation of long-chain fatty acid uptake, protein synthesis, and vascular tonicity. Significant advancements have been made over the last 20 years in the understanding of the signal transduction elements involved in these insulin effects. Among these molecular mechanisms, the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway is thought to play a crucial role. Under pathological conditions, such as type-2 diabetes, myocardial ischaemia, and cardiac hypertrophy, insulin signal transduction pathways and action are clearly modified. These molecular signalling alterations are often linked to atypical crosstalks with other signal transduction pathways. On the other hand, pharmacological modifications of parallel and interdependent signalling components, such as the AMP-activated protein kinase pathway, are now considered to be a good therapeutic approach to treat insulin-signalling defects such as insulin resistance and type-2 diabetes. In this review, we will focus on the description of the molecular signalling elements involved in insulin action in the heart and vasculature under these different physiological, pathological, and therapeutical conditions.