Septins form a cytosolic protein family gaining recognition as important effectors in molecular mechanisms involving membrane rearrangements, such as cytokinesis and exocytosis. So far, twelve different members of the family (named SEPT1 to SEPT12) have been characterized in mammals, and their roles are not limited to those mentioned above, but embrace a large number of physiological and pathophysiological events. In particular, reports have associated septins with cancer, apoptosis and neurodegenerative diseases. In this study, we further characterize the platelet septin, SEPT5 (formerly CDCrel-1) as a regulator of platelet physiology. SEPT5 is highly expressed in megakaryocytes, heart and brain and is directly linked to secretion mechanisms in both platelets and neurons. In neurons, SEPT5 negatively modulates neurotransmitter release and has recently been implicated in mechanisms leading to development of schizophrenia in rat models. In platelets, we and others have shown that SEPT5 is preferentially located around α-granules and associates with syntaxin 4 and other members of the septin protein family (SEPT4 and SEPT8) to form a cytoplasmic macromolecular complex. Work from other laboratories has linked SEPT5 to different members of the SNARE family such as syntaxin 1A, the sec6/8 complex, and SNAP25. We have found the overexpression of mouse SEPT5 is associated with fewer α-granules but those present are larger in size suggesting levels of Sept5 maintain normal α-granule size. In a murine model of SEPT5 deficiency, platelets display an increased sensitivity to platelet agonists such as collagen and the thromboxane analogue U46619. To date, SEPT5 is the only mammalian septin whose relevance has been tested in a mouse knockout model. Our current studies use a lumi-aggregometer to document the active secretion of ATP in SEPT5 deficient platelets. Platelets lacking SEPT5 are more responsive to submaximal concentrations of acid insoluble fibrillar type I collagen (< 2.5 mg/mL). We observe a 2- to 3-fold increase in ATP secretion in deficient platelets as compared to their wild-type littermates. The increased dense granule release in the absence of SEPT5 also coincides with increased platelet aggregation. A maximum release of ATP was determined in the presence of the calcium ionophore (A23187, 40μM). Higher concentrations of collagen (5 μg/ml) produced a maximum level of ATP release in SEPT5 deficient mice unlike their wild-type littermates. Our current hypothesis places SEPT5 as a scaffolding protein that serves to anchor other proteins into higher-ordered molecular complexes. SEPT5 biology in platelets needs to be further studied to fully understand its role in granule secretion and formation. While important for platelet biology, these studies may also have implications for mechanisms associated with neurotransmitter release. As such, the platelet becomes an excellent model for analyzing SEPT5 function with implications for hemostasis and beyond.