The current diagnosis of lymphoid neoplasias is based on the criteria of the World Health Organization (WHO) classification. This framework is built on two major principles: the stratification of neoplasms according to their derivation from precursor or mature cells and the definition of clinically relevant nonoverlapping diseases. The diagnosis is established by integrating the clinical, morphological, phenotypic, genetic and molecular characteristics of the tumors. This approach is reproducible, clinically relevant and scientifically sound. The elucidation of the human genome a decade ago and the development of high-throughput technologies have opened the possibility to search for comprehensive views of the genomic alterations of the tumors that are starting to influence our current approach to diagnosis. The new generation of sequencing technologies and their systematic application to human cancer and in particular to lymphoid neoplasms are revealing a landscape of somatic mutations of unprecedented complexity. These studies have already provided a number of important findings with functional and clinical implications. The translation of all this knowledge into the clinic is challenging and offers relevant perspectives.