Metastases are the major cause of cancer-related deaths in patients with solid epithelial malignancies, such as breast, colorectal and prostate carcinomas. Hematogenous spreading of tumor cells from a primary tumor can be considered as a crucial step in the metastasis cascade leading eventually to the formation of clinically manifest metastases. Consequently, as shown in recent studies, the detection of disseminated tumor cells in peripheral blood might be of clinical relevance with respect to individual patient prognosis and staging or monitoring of therapy. However, the rarity of disseminated tumor cells in peripheral blood renders the application of sensitive techniques mandatory for their detection. The emergence of highly sophisticated reverse transciptase-polymerase chain reaction (RT-PCR) assays, combining a preanalytical enrichment step with the assessment of multiple molecular tumor markers expressed in disseminated tumor cells, provides a powerful tool in detecting disseminated tumor cells with high sensitivity and specificity. This review will discuss currently used tumor markers as well as experimental means to enhance the sensitivity and specificity of RT-PCR assays to detect disseminated tumor cells in the peripheral blood of patients with breast, colorectal, and prostate cancers, and their clinical relevance assessed in recent studies.