Psychological attitudes are prospectively related to cardiovascular disease (CVD), but a causal relationship has not been demonstrated. Trait optimism/pessimism (positive or negative future expectation, respectively), and cynical hostility (mistrust of people), are attitudes with features of personality traits. These attitudes may affect CVD risk in several ways, by influencing an individual's (1) adoption of health behaviors, (2) maladaptive stress responding resulting in direct alteration of physiology (i.e., autonomic dysfunction, thrombosis, arrhythmias), (3) development of traditional CVD risk factors, and (4) lack of adherence to therapy in both primary and secondary prevention. More adaptive attitudes may favorably influence CVD risk at each of these critical junctures. The genetic and environmental (i.e., social, economic, racial/ethnic) determinants of attitudes have not been extensively studied. In addition, it is important to understand how some of these environmental determinants may also moderate the association between attitudes and CVD. Clinical trials to modify attitudes for CVD risk reduction (either by reducing negative attitudes or by increasing positive attitudes) are difficult to conduct, but are necessary to determine whether attitudes can indeed be modified, and if, so, to quantify any CVD-related benefits. To address these questions we present a broad, multidisciplinary research agenda utilizing mixed methods and integrating principles of epidemiology, genetics, psychophysiology, and behavioral medicine over the lifecourse (first figure). This overview focuses on attitudes and CVD, but has broader implications for understanding how psychological factors relate to chronic diseases of adulthood.