Metastatic disease is the most important determinant in the clinical management of patients with cancer. Disseminated tumor cells are regarded as a surrogate for early metastatic spread of disease. These cells can be detected in bone marrow aspirates, lymph nodes and peripheral blood, where we refer to them as circulating tumor cells. Detection of disseminated tumor cells represents a great technical challenge, and many different technologies have been developed to enhance the sensitivity and specificity of the testing for these rare events. Different characteristics of tumor cells have been used to establish enrichment methods, including the differential expression of tumor-specific markers on the surface of the cells, the size-based selection of the cells, and other physical properties. Despite technical obstacles, the detection of circulating tumor cells in particular have emerged in recent years as a biomarker with outstanding predictive and prognostic capacity in a number of malignancies including breast, prostate, lung and colorectal cancer. In this text, we provide a comprehensive review of different approaches for enrichment of disseminated and circulating tumor cells and elucidate additional molecular methods for their detection. Further, the clinical significance of disseminated tumor cells detected in various compartments is discussed. Based on recent findings on the biology and heterogeneity of tumor cells, along with development of robust enrichment techniques, we believe that future research will focus less on pure detection but more importantly on detailed molecular characterization of these rare events with the potential impact on design of novel therapeutics.