B-cell malignancies account for over the 90% of all lymphoid neoplasms. The clonal proliferations of B-cells show a high degree of variation in terms of clinical and presenting features, histopathology, immuophenotype, and genetics. Primary tumor samples are useful for examining the characteristics of a patients own tumor, although both primary leukemic cells and cell lines provide an initial step for screening novel compounds for their activity in some hematological malignancies, they should be followed by models in intact animals. In this review, we try to summarize the animal models generated to study B-cell malignancies, in particular, B-cell lymphoma, B-cell CLL and MM that represent the major part of B-cell malignancies. Animals that spontaneously develop cancer are flawed to predict human disease. The development of human tumor xenograft models represented a big step towards more clinically relevant models. The major problems of these models are the requirement of immunocompromised animals and the inability of these models to recapitulate the complex relationship between the tumor and the microenvironment. A number of strategies have been also applied to develop genetically engineered models of malignancies, in which the tumor arises “naturally” in the host. The disadvantages of these models include the differences between rodent and human stroma and that they can not be used to characterise anti-tumor activity of many immunotherapeutic drugs. These models can be used to study the molecular processes critical for the development, proliferation and survival of hematological malignancies and to characterise potential therapeutic targets.