Molecular cancer biomarkers are any measurable molecular indicator of risk of cancer, occurrence of cancer, or patient outcome. They may include germline or somatic genetic variants, epigenetic signatures, transcriptional changes, and proteomic signatures. These indicators are based on biomolecules, such as nucleic acids and proteins, that can be detected in samples obtained from tissues through tumor biopsy or, more easily and non-invasively, from blood (or serum or plasma), saliva, buccal swabs, stool, urine, etc. Detection technologies have advanced tremendously over the last decades, including techniques such as next-generation sequencing, nanotechnology, or methods to study circulating tumor DNA/RNA or exosomes. Clinical applications of biomarkers are extensive. They can be used as tools for cancer risk assessment, screening and early detection of cancer, accurate diagnosis, patient prognosis, prediction of response to therapy, and cancer surveillance and monitoring response. Therefore, they can help to optimize making decisions in clinical practice. Moreover, precision oncology is needed for newly developed targeted therapies, as they are functional only in patients with specific cancer genetic mutations, and biomarkers are the tools used for the identification of these subsets of patients. Improvement in the field of cancer biomarkers is, however, needed to overcome the scientific challenge of developing new biomarkers with greater sensitivity, specificity, and positive predictive value.