Tumor biomarkers, substances produced by tumors or the body's response to tumors, play a critical role in cancer diagnosis, prognosis, and targeted therapy. Over the past decades, significant progress has been made in discovering novel, sensitive, and specific biomarkers, enhancing personalized medicine and improving cancer outcomes. This review summarizes the history, technologies, and applications of tumor biomarkers, highlighting recent advancements in biomarker-based targeted therapies. It also discusses challenges and opportunities in this field. Tumor biomarkers have evolved from early discoveries like Bence-Jones protein (1846) to modern molecular technologies, including genomics, transcriptomics, proteomics, and CRISPR/Cas9. These technologies enable large-scale biomarker discovery and detection, improving early cancer screening, diagnosis, prognosis, and recurrence monitoring. For example, AFP is used for hepatocellular carcinoma (HCC) screening, while CEA is used in various cancers. Recent innovations, such as liquid biopsy, allow non-invasive detection of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), enhancing early detection and treatment monitoring. Technologies like RIA, FIA, molecular hybridization, PCR, DNA sequencing, IHC, and electron microscopy have been developed for biomarker detection. Each technology has unique advantages, such as RIA's high sensitivity, FIA's non-isotopic detection, and PCR's ability to amplify DNA for mutation analysis. DNA sequencing, particularly next-generation sequencing (NGS), has revolutionized cancer genomics, enabling the identification of mutations and biomarkers for personalized treatment. IHC is a gold standard for cancer diagnosis, while electron microscopy provides ultrastructural insights into tumor cells. Tumor biomarkers are classified by tissue origin, including those from blood, tissues, and other biofluids. Blood-derived biomarkers like AFP, CEA, SCCA, TPS, and PSA are widely used for cancer diagnosis and monitoring. However, challenges remain in terms of sensitivity, specificity, and clinical utility. Future research aims to improve biomarker discovery and integration into personalized medicine, enhancing cancer treatment outcomes.Tumor biomarkers, substances produced by tumors or the body's response to tumors, play a critical role in cancer diagnosis, prognosis, and targeted therapy. Over the past decades, significant progress has been made in discovering novel, sensitive, and specific biomarkers, enhancing personalized medicine and improving cancer outcomes. This review summarizes the history, technologies, and applications of tumor biomarkers, highlighting recent advancements in biomarker-based targeted therapies. It also discusses challenges and opportunities in this field. Tumor biomarkers have evolved from early discoveries like Bence-Jones protein (1846) to modern molecular technologies, including genomics, transcriptomics, proteomics, and CRISPR/Cas9. These technologies enable large-scale biomarker discovery and detection, improving early cancer screening, diagnosis, prognosis, and recurrence monitoring. For example, AFP is used for hepatocellular carcinoma (HCC) screening, while CEA is used in various cancers. Recent innovations, such as liquid biopsy, allow non-invasive detection of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), enhancing early detection and treatment monitoring. Technologies like RIA, FIA, molecular hybridization, PCR, DNA sequencing, IHC, and electron microscopy have been developed for biomarker detection. Each technology has unique advantages, such as RIA's high sensitivity, FIA's non-isotopic detection, and PCR's ability to amplify DNA for mutation analysis. DNA sequencing, particularly next-generation sequencing (NGS), has revolutionized cancer genomics, enabling the identification of mutations and biomarkers for personalized treatment. IHC is a gold standard for cancer diagnosis, while electron microscopy provides ultrastructural insights into tumor cells. Tumor biomarkers are classified by tissue origin, including those from blood, tissues, and other biofluids. Blood-derived biomarkers like AFP, CEA, SCCA, TPS, and PSA are widely used for cancer diagnosis and monitoring. However, challenges remain in terms of sensitivity, specificity, and clinical utility. Future research aims to improve biomarker discovery and integration into personalized medicine, enhancing cancer treatment outcomes.