Prolonged sitting and sedentary behavior comprises a major part of the modern lifestyle: at work, leisure (watching television, Internet) and commuting/traveling. Studies have shown that adults spend about half of their time at work and even more sitting. Similarly, a significant part of the leisure time is spent doing sedentary activities usually in front of a screen (TV or a computer). However, current recommendations focus on increasing moderate-to-vigorous physical activity with almost no recommendations relating to sedentary activities. Recent evidence from several research papers showed deleterious relationships of sedentary behavior with cardiovascular risk factors (e.g., obesity, type 2 diabetes mellitus and waist circumference). Furthermore, consistent independent associations have been observed between sitting time/sedentary behaviors and elevated all-cause and cardiovascular disease mortality risk. Generally, these associations have persisted following adjustment for physical activity. Recent emerging findings have shown that breaking up sedentary time potentially has a beneficial impact on cardiovascular health (independent of total sedentary time and moderate-to-vigorous intensity activity). In this article, we review the association between the time spent in various sedentary activities (occupational, leisure and commuting/transportation) and cardiovascular risk factors and cardiovascular morbidity and mortality. In addition, we review the suggested mechanisms that explain the empiric associations.