Cancer is the second most extended disease with an improved death rate over the past several time. Due to the restrictions of cancer analysis methods, the patient's real survival rate is unknown. Therefore, early stage diagnosis of cancer is crucial for its strong detection. Bio-analysis based on biomarkers may help to overcome the problem Biosensors with high sensitivity and specificity, low-cost, high analysis speed and minimum limit of detection are practical alternatives for laboratory tests. Surface plasmon resonance (SPR) is reaching a maturity level sufficient for their application in detection and determination cancer biomarkers in clinical samples. This review discusses main concepts and performance characteristics of SPR biosensor. Mainly, it focuses on newly emerged enhanced SPR biosensors towards high-throughput and ultrasensitive screening of cancer biomarkers such as PSA, α-fetoprotein, CEA, CA125, CA 15-3, HER2, ctDNA, ALCAM, hCG, VEGF, TNF, Interleukin, IFN-γ, CD24, CD44, Ferritin, COLIV using labeling processes with focusing on the future application in biomedical research and clinical diagnosis. This article reviews current status of the field, showcasing a series of early successes in the application of SPR for clinical bioanalysis of cancer related biomolecules and detailing a series of considerations regarding sensing schemes, exposing issues with analysis in biofluids, while providing an outlook of the challenges currently associated with plasmonic materials, bioreceptor selection, microfluidics, and validation of a clinical bioassay for applying SPR biosensors to clinical samples. Research opportunities are proposed to further advance the field and transition SPR biosensors from research proof-of-concept stage to actual clinical usage.