Cardiovascular disease (CVD) is a broad definition for diseases of the heart and blood vessels with high mortality and morbidity worldwide. Atherosclerosis and hypertension are the most common causes of CVD, and multiple factors confer the susceptibility. Some of the predisposing factors are modifiable such as diet, smoking, and exercise, whereas others, including age, sex, and genetic composition are non-modifiable. Interactions between the different factors also contribute to the outcome. Development of cardiovascular disease starts in childhood and gradually involves multiple organs, tissues, and cell types with different functions. The molecular mechanisms underlying CVD are estimated to involve hundreds of genes. To better address the highly complex architecture and multiple properties leading to CVD, networks and systems approaches combining information at genomic, transcriptomics, methylomics, proteomics, metabolomics, and phenome level are being developed, with the ultimate goal to elucidate the cascade of dynamic changes leading to CVD in humans. This review will discuss co-expression networks and systems approaches from cardiovascular genetics point of view.