Phosphoinositide 3-kinases (PI3Ks) are protein and lipid kinases activated by different classes of membrane receptors, including G-protein coupled and tyrosine kinase receptors. Several lines of evidence have uncovered specific roles for distinct PI3K isoforms in the vascular system in both physiology and disease. The present review will summarize and discuss the most recent advances regarding PI3K-Akt signalling in endothelial cells, vascular smooth muscle cells, platelets, and inflammatory cells involved in the atherosclerotic process. Of interest, the development of novel isoform-selective PI3K inhibitor drugs offers a unique opportunity to selectively and differentially target PI3K-driven pathways in the vascular system and may give rise to new strategies for the treatment of cardiovascular diseases.