Cytosolic free calcium (Ca2+) is a second messenger regulating a wide variety of functions in blood cells, including adhesion, activation, proliferation and migration. Store-operated Ca2+ entry (SOCE), triggered by depletion of Ca2+ from the endoplasmic reticulum, provides a main mechanism of regulated Ca2+ influx in blood cells. SOCE is mediated and regulated by isoforms of the ion channel proteins ORAI and TRP, and the transmembrane Ca2+ sensors stromal interaction molecules (STIMs), respectively. This report provides an overview of the (patho)physiological importance of SOCE in blood cells implicated in thrombosis and thrombo-inflammation, i.e. platelets and immune cells. We also discuss the physiological consequences of dysregulated SOCE in platelets and immune cells and the potential of SOCE inhibition as a therapeutic option to prevent or treat arterial thrombosis as well as thrombo-inflammatory disease states such as ischemic stroke.