ABSTRACT How genetic variations mediate normal and abnormal biological function is a major issue in biology and medicine. The enormous number of genomic sequences, and their frequent and rare variations identified in humans, require efficient approaches aimed at dissecting functional correlates. In this review we will focus on the importance of the assessment of well-defined intermediate phenotypes, on the set up of transcriptomic approaches in diseased cells and on the modulation of expression by sequence variations modulating mRNA splicing or influencing protein multimerization. These information provide the molecular bases of associations discovered through genomic approaches, and might open new avenues toward the design of novel and specific diagnostic, prophylactic or therapeutic interventions. Taking into account our previous and current experimental activities we shall focus on a few examples and open issues in cardiovascular disorders, the main clinical topic of this short review.