The complete human genome sequencing project opened the route to a new holistic scientific movement, characterised by the investigation of the functional elements of our genetic heredity mainly in respect to multifactorial diseases such as cancer, diabetes, dementias, etc. The clinical proteomics tries to highlight the relationships between the main molecular physiological effectors, proteins, with defined physiopathological conditions. The development of a new generation of mass spectrometers is deeply changing the technologies employed in these investigations, enabling direct quantitative analysis of clinical samples such as, blood, urine, saliva and biopsy samples. In this manuscript we introduce and discuss the main phases of these investigations and their possible follow up in diagnostic and functional studies.