The relative scarcity of Hodgkin (H) and Reed-Sternberg (RS) cells within biopsies from cases with Hodgkin's disease (HD) is an impediment to the analysis of the nature and function of these cells. Continuous cell lines as uniform and permanently available sources of cells provide a valid alternative. Development of HD cell lines has proven to be rather difficult when compared with the results on leukemia and Non-Hodgkin lymphoma cells. Only a few cell lines containing cells that resemble in-vivo H-RS cells have been established. Because the in-vitro culture conditions favor the self-propagation of residual normal cells, e.g. Epstein-Barr virus transformed B-lymphoblastoid cells or monocyte/macrophage monolayers, early attempts at culturing HD tissue resulted mainly in the generation of such cell lines. Even for the bona fide HD cell lines it is difficult to prove that the immortalized cells originated from an H-RS cell. These 13 HD cell lines have been extensively characterized in a large variety of aspects. These data have resulted in widely varying conclusions about the nature of the cell lines. It is apparent that all HD cell lines are unique among hematopoietic cell lines and are also different from one another. No conclusive evidence towards the origin of the cells has been obtained for some cell lines, while others could be operationally, albeit not always unequivocally, assigned to the T- or B-cell or monocyte-macrophage lineages. The overall phenotypes are often not concordant with those of normal hematopoietic cells; some cell lines show clearly mixed lineage attributes. The artifactual expansion of non-HRS cells in culture and the acquisition or loss of certain properties during the adaptation to culture systems cannot be excluded. There was also a bias for the establishment of cell lines from cases with advanced clinical stages, nodular sclerosing subtype and pleural effusions. The extensive analysis of a few cell lines has provided a wealth of information useful for the understanding of the biology of H-RS cells. The striking heterogeneity could be reflective of a biologically heterogeneous disease.