PI3Ks are signaling enzymes engaged by different types of membrane receptors and activated in cardiovascular diseases such as hypertension, atherosclerosis, thrombosis and heart failure. Studies performed on genetically modified animals have provided proof-of-concept that general or isoform-specific blockade of these enzymes can modify disease development and progression. Hence, therapeutic inhibition of PI3Ks with novel pharmacological compounds constitutes a promising area of drug development. In particular, inhibitors of PI3Ks have the potential to reduce blood pressure, restrain the development of atherosclerosis and/or stabilize atherosclerotic plaques, blunt platelet aggregation, prevent left ventricular remodeling and preserve myocardial contractility in heart failure. This review summarizes the rationale of PI3K inhibition in the most prevalent cardiovascular diseases, and the available data on the therapeutic effects of PI3K inhibitors in their preclinical models. Implications for future drug development and human therapy are also discussed.