Cardiovascular diseases, including atherosclerotic disease and its thrombotic complications are one main cause of hospitalization and mortality in the world. The family of phosphoinositide 3-kinases (PI3Ks) play an important role in the pathogenesis of cardiovascular diseases by regulating essential cellular functions, such as cell migration, translational responses, and cell survival, and thereby, modulating several essential biologic processes, such as metabolism, vascular homeostasis and thrombogenicity. PI3Ks can be divided into three classes, of which the class I-group is the best characterized. This group consists of four isoforms, named PI3Kα, β, δ, and γ. Each isoform has distinct functions under normal as well as pathophysiologic conditions. The development of several pharmacologic isoform-selective, isoform-preferring, and pan-PI3K inhibitors enlarged and potentiated the knowledge about the effect of the different PI3K isoforms on specific biologic processes as well as their role under pathophysiologic conditions. Moreover, this offered the possibility for novel therapeutic strategies targeting PI3K isoforms in cardiovascular diseases. Therefore, this review will focus on the pathophysiologic role of class I PI3Ks in cardiovascular diseases as well as on the therapeutic potential of pharmacological PI3K inhibitors for the treatment of this scourge of humanity.