B–lymphomas develop and progress in a specialized tissue microenvironment such as bone marrow or secondary lymphoid organs such as lymph node and spleen. While malignant neoplasmswere long considered diseases defined and driven by genomic instability, chromosomal alterations, and genetic mutations, today influence of nonmalignant, stromal cells of the tumour microenvironment is also appreciated. The lymphoma microenvironment is characterized by a heterogeneous population of stromal cells, including fibroblastic reticular cells, mesenchymal stem cells, follicular dendritic cells, and inflammatory cells such as macrophages, T–and B–cells. These cell populations interact with malignant cells and promote lymphoma growth, survival and drug resistance through multiple mechanisms. In the context of malignant progression, the tumour microenvinronment has multifaceted ability to influence therapeutic outcome in either a positive or a negative manner. Advanced laboratory techniques and bioinformatic tools can differ subpopulations in complex tumor tissues and thus identify factors important in tumor and non-tumor cell communication in order to provide new insights into potential ‘doublehit’ therapeutic strategies.