The proteome is described as the entirety of all proteins expressed within a cell at a given moment. In contrast to the stability of the genome, the proteome is highly dynamic and reflects the cells current status. Since proteins carry out almost all biological functions, the proteome stands in direct relation to cellular functions. Proteomic analysis (i.e., two-dimensional electrophoresis, mass spectrometry and bioinformatics) aims at identifying changes in the composition of the proteome associated to pathophysiologic events that affect basic cellular functions. Functional proteomics expands to understanding the connection between proteomic changes and the state of a cell, taken into account that the observed modifications can be either cause or consequence of the pathological state. Proteomics will not only improve our basic understanding of the factors and molecular mechanisms underlying cardiovascular disease, but also will help identifying novel diagnostic markers and fuel the rational design and discovery of new drugs for medical intervention. This review will discuss basic proteomic approaches relevant to cardiovascular disease, as well as their applications for the identification of biomarkers and drug design.