Receptor signaling relays on intracellular events amplified by secondary and tertiary messenger molecules. In cardiomyocytes and smooth muscle cells, cyclic AMP (cAMP) and subsequent calcium (Ca2+) fluxes are the best characterized receptor-regulated signaling events. However, most of receptors able to modify contractility and other intracellular responses signal through a variety of other messengers, and whether these signaling events are interconnected has long remained unclear. For example, the PI3K (phosphoinositide 3-kinase) pathway connected to the production of the lipid second messenger PIP3/PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-trisphosphate) is potentially involved in metabolic regulation, activation of hypertrophy, and survival pathways. Recent studies, highlighted in this review, started to interconnect PI3K pathway activation to Ca2+ signaling. This interdependency, by balancing contractility with metabolic control, is crucial for cells of the cardiovascular system and is emerging to play key roles in disease development. Better understanding of the interplay between Ca2+ and PI3K signaling is, thus, expected to provide new ground for therapeutic intervention. This review explores the emerging molecular mechanisms linking Ca2+ and PI3K signaling in health and disease.