Like other B-cell lymphomas, the development and progression of follicular lymphoma (FL) involves complex interactions between the neoplastic B cells and the surrounding microenvironment. Malignant B cells can manipulate the microenvironment by skewing the differentiation of immune cells, attracting regulatory T cells or suppressive monocytes, or secreting cytokines that promote an immunosuppressive environment. The importance of the microenvironment in FL has been demonstrated using methodologies such as gene expression profiling, which has shown that the nature of the tumor microenvironment predicts survival in patients with FL and may influence the response to immunotherapy and risk of transformation. Strategies that both enhance an effective antitumor response and reverse immunosuppression and dysfunction will be essential in the development of effective immunotherapeutic approaches in this disease.