Introduction Platelets are small, anucleate, cells which travel as resting discoid fragments in the blood circulation. Upon contact with an injured blood vessel, they prevent blood loss through processes of adhesion, activation and aggregation. Platelets play a central role in cardiovascular disease (CVD), both in the development of atherosclerosis and in the development of acute thrombotic events. CVD risk factors can be classed as modifiable or non-modifiable. This thesis focuses on the effect of the modifiable risk factors (physical inactivity, overweight/obesity and low cardiorespiratory fitness (CRF)) on platelet function. We investigate the role of acute exercise on platelet function, and the impact of CRF on platelet responses to acute exercise. We also explore the role of microRNA (miRNA), a subset of small non-coding RNA, in regulating platelet function in response to physical inactivity. Hypothesis Physical inactivity, overweight/obesity and low CRF adversely impact platelet function. miRNA expression could influence and modulate the platelet function response to physical inactivity. Results We performed a cross-sectional study to investigate the relationship between platelet function and lifestyle factors. High platelet counts and plateletcrit were associated with less favourable cardiovascular risk profiles, in particular with measures of overweight. Platelet adhesion was significantly increased in subjects with an overweight BMI compared to those with a healthy weight BMI. Acute strenuous aerobic exercise resulted in increased platelet adhesion and aggregation in adults and adolescents. This increase was more pronounced in those with a low CRF, particularly in adolescent subjects. Using a Dry Immersion (DI) model, we investigated the effect of acute physical inactivity on platelet function in 12 healthy males. Three days of DI resulted in significant increases in platelet count, plateletcrit, platelet adhesion, aggregation, and an elevation of platelet reactivity index (PRI) and microvesicle concentration. We identified 15 cardiovascular and inflammatory protein biomarkers whose expression levels were altered after physical inactivity. We also identified a set of 22 ‘physical inactivity’ related miRNA, which have potential targets involved in pathways associated with platelet function. Conclusion Modifiable CVD risk factors of overweight/obesity and physical inactivity elicit a prothrombotic platelet profile. CRF levels affect the platelet response to acute exercise, suggesting that habitual physical activity influences platelet function. miRNA expression can influence and modulate the platelet function response to physical inactivity by negative regulation of gene expression and could act as markers of megakaryocyte epigenetic drift.