The detection and elimination of minimal systemic disease in patients with solid tumors is one of the main current topics in clinical oncology. The present review focuses, therefore, on new diagnostic approaches to identify minimal disease in peripheral blood, bone marrow, and lymph nodes of patients with epithelial cancer as the major type of solid tumors in Western industrialized countries. These approaches may be used to improve tumor staging and monitoring of adjuvant therapies, as well as to detect tumor cell contamination in autologous stem cell grafts. Most investigators have developed either immunocytochemical assays with monoclonal antibodies to a variety of epithelial-specific cytoskeleton and membrane antigens or molecular methods based on the extensive amplification of a specific (c)DNA sequence by the polymerase-chain reaction (PCR). In immunocytochemical assays, antibodies to cytokeratins can be regarded as the most specific and sensitive probes to detect isolated epithelial tumor cells in bone marrow and blood. Molecular methods are based on the detection of either mutations in oncogenes and tumor suppressor genes (e.g., ki-ras and p53 genes) or the mRNA expression of tissue-specific and tumor-associated genes. mRNA species targeted in these assays encode cytokeratins, prostate-specific antigen, prostate-specific membrane antigen, carcinoembryonic antigen, and polymorphic-epithelial mucin. To introduce the available methods into clinical practice, standardized protocols need to be developed and validated in multi-center studies.