Cancer is one of the three leading causes of death worldwide. Even after successful therapy and achieving remission, the risk of relapse often remains. In this context, dormant residual cancer cells in secondary organs such as the bone marrow constitute the cellular reservoir from which late tumor recurrences arise. This dilemma leads the term of minimal residual disease, which reflects the presence of tumor cells disseminated from the primary lesion to distant organs in patients who lack any clinical or radiological signs of metastasis or residual tumor cells left behind after therapy that eventually lead to local recurrence. Disseminated tumor cells have the ability to survive in a dormant state following treatment and linger unrecognized for more than a decade before emerging as recurrent disease. They are able to breakup their dormant state and to readopt their proliferation under certain circumstances, which can finally lead to distant relapse and cancer-associated death. In recent years, extensive molecular and genetic characterization of disseminated tumor cells and blood-based biomarker has contributed significantly to our understanding of the frequency and prevalence of tumor dormancy. In this article, we describe the clinical relevance of disseminated tumor cells and highlight how latest advances in different liquid biopsy approaches can be used to detect, characterize, and monitor minimal residual disease in breast cancer, prostate cancer, and melanoma patients.