Surface enhanced laser desorbtion/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS or SELDI) combines retentate chromatography and mass spectrometry in a high-throughput format. Analytes are captured using chromatographic or immunocapture surfaces, matrix applied, ionised/desorbed with a laser and mass spectra acquired. SELDI based proteomics detects peptides and small proteins ( < 20 kDa) and may be used to study the concentrations, modifications and interactions of specific proteins or to discover proteomic changes associated with any biological condition of interest. Over the last decade SELDI has been applied to a wide range of biological samples but most often in the search for blood-borne biomarkers of human diseases, especially cancers. As with any biomarker research many pitfalls such as insufficient sample size, insufficient quality control, overfitting and bias must be carefully avoided to provide meaningful results. Initially, very promising results were obtained using SELDI-based ‘proteomic profiling’ to detect cancer. However, nearly 10 years on from these initial reports, none of the potential biomarkers discovered by this approach have entered routine clinical practice. It is now apparent that SELDI analysis of serum predominantly detects abundant serum proteins and that ‘biomarkers’ detected in SELDI experiments most likely arise from host responses to the cancer. SELDI therefore stands at a crossroads: will some of the biomarker work to date withstand further validation and help in the development of clinical tests, will advances in the technology allow deeper proteome mining or will SELDI become obsolete as a biomarker discovery platform? We review what has been achieved by SELDI both in, and outside, of the context of biomarker discovery.