Early detection and definitive treatment of cancer have been shown to decrease death and suffering in epidemiologic and intervention studies. Application of genomic approaches to many malignancies has produced thousands of candidate biomarkers for detection and prognostication, yet very few have become established in clinical practice. Fundamental issues related to tumor heterogeneity, cancer progression, natural history, and biomarker performance have provided challenges to biomarker development. Technical issues in biomarker assay detection limits, specificity, clinical deployment, and regulation have also slowed progress. The recent emergence of biomarkers and molecular imaging strategies for treatment selection and monitoring demonstrates the promise of cancer biomarkers. Organized efforts by interdisciplinary teams will spur progress in cancer diagnostics.