Cancers represent a major class of morbidity and the primary cause of death in the segment of active population. Improvement of therapeutically outcomes depends on more precise and earlier diagnostics, and biomarkers discovery and validation are considered the key for this, and also an essential tool in drug discovery. Omics technologies are intensely involved in biomarkers research. SELDI-TOF mass spectrometry combines flexibility, resolving power and sensitivity with high throughput potential, generating a suitable proteomic platform for research and clinical applications. SELDI platforms have been used to identify protein biomarkers in a variety of cancers, resulting in promising diagnostic strategies. Outcomes of SELDI technology in protein profiling of different samples prove its resources and reliability in biomarkers discovery, and recommend it as a major clinical tool of the future. Significant results obtained in pancreatic, colon, cervical, breast and brain tumors have been described. Relevant proteomic signatures could be identified in different sample types, setting up potential diagnostics and/or prognostics instruments for various cancers. Success in validation has already been achieved in some cases, yet the overall conclusion is that SELDI technology represents one component of a broader spectrum of versatile investigation technologies that may finally lead to setting up a more "clinical friendly" set of dedicated diagnostics tools.