There is growing evidence suggesting that cross talk between mantle cell lymphoma (MCL) cells and stromal cells in tissue microenvironments, such as the bone marrow and secondary lymphoid organs, causes disease progression by promoting lymphoma cell survival, growth, and drug resistance. Conceivably, while conventional treatment eliminates the bulk of MCL cells, residual lymphoma cells may lurk in protective tissue niches, where they receive signals from accessory cells that promote survival and drug-resistance, thereby paving the way for residual disease and relapses. Based on this concept, the lymphoma microenvironment has become a growing area of current research, and initial clinical trials targeting cross talk between MCL cells and their microenvironment are showing promising early results. In this review, we summarize key cellular and molecular interactions between MCL cells and their microenvironment, and update new clinical developments in this area.