BACKGROUND: Aging is closely related to the onset of chronic diseases, such as coronary artery disease, diabetic nephropathy or different types of malignancies, reflecting the demand for novel biomarkers to manage theses diseases. OBJECTIVE: The analysis of the human proteome for biomarkers has made considerable advances in the last years. METHODS: We describe the main technological approaches taken, their advantages and disadvantages. RESULTS: We will review the different clinical sources of material and attempt to highlight the different challenges and approaches associated with these. Age-related changes in the proteome have been described and were found to be highly similar to changes associated with chronic diseases. We will give several examples on the successful application of proteomics in the diagnosis, prognosis and therapy of these chronic diseases. CONCLUSIONS: A boost in disease-related proteomic information is expected in the very near future, and will also result in its broad clinical application. However, this view appears to be dependent on the strict adherence to proper technological/analytical parameters, correct statistics, and large databases that allow comparison of datasets provided by different scientists. Clearly, the proteome is by far too complex to be tackled by one laboratory on its own.