The potential role of genetic variations in the pathogenesis of cardiovascular diseases is a field of continuous investigation and the perception of the role of genes has dramatically changed during the last 20 years. The two more commonly used experimental designs, based on a candidate gene or a genome wide approach, have been somehow replaced by the possibility to build haplotypes in the context of a single gene using a so-called gene-wide approach. Human diseases, however, are far from theoretical and in silico speculation and the analysis of the contribution of the individual genetic background to their pathogenesis still needs a working hypothesis that, starting from the patho-physiology of the disease under investigation, takes advantage of the newly available technologies and software. In this perspective, the gene-wide approach may represent an attractive methodology to bridge the gap between bench and bedside. Here we review the rationale behind this approach, the available methodologies and the potential clinical applications.