Diffuse aggressive B-cell lymphomas comprise a relatively common and increasingly diverse group of neoplasms. Newer modalities including gene expression profiling and an increasing panel of immunohistochemical markers have contributed to greater accuracy in defining these entities. Attention is paid not only to the neoplastic cells but also to the cellular and stromal milieu in which they proliferate. These distinctions may have therapeutic implications as well, with improved outcome related to newer and sometimes targeted therapies. At the same time there is increasing understanding of the overlap, which occurs in the grey zone between diffuse large B-cell lymphoma and Burkitt lymphoma as well as between diffuse large B-cell lymphoma and Hodgkin lymphoma. This review aims to provide practical insights in the correct identification and differential diagnosis of these lymphomas, with emphasis on the changes that have occurred with the publication of the 2008 World Health Organization updated classification.