The field of molecular diagnostics is changing and adapting to new information obtained from genetic, genomic and proteomic profiling of diseases. One of the novel technologies that has made significant impact on the molecular diagnosis of lymphoid malignancies is DNA microarray technology. It has allowed the profiling of the most common types of lymphomas, identifying distinct molecular signatures of these diseases as well as novel subtypes that cannot otherwise be identified by conventional methods. In addition, it has also allowed the construction of molecularly defined prognostic models for various types of lymphomas and to better understand the molecular mechanisms that determine the behavior of the tumor. In this review, recent advances in the molecular diagnosis of diffuse large B-cell lymphoma are highlighted, using examples of how gene expression profiling has been used in disease classification and outcome predictions. The future development of this field and its applications in the clinical arena will also be discussed.