Posttranslational modifications (PTMs) such as protein arginine methylation are involved in the regulation of diverse cellular processes such as epigenetic modifications, DNA damage response (DDR), RNA processing, signal transduction, and immune responses. Protein methyltransferases (PRMTs), which mediate arginine methylation, have been studied because of their dysregulation in several diseases. PRMT5, a type II arginine methyltransferase is relevant to cancer progression. Inhibition/deletion of PRMT5 augments tumor immunity by modulating Tip60 histone acetyltransferase activity and FOXP3 levels and limits the inhibitory function of T regulatory (Treg) cells, providing an approach to treat human cancers in an effective and exclusive manner. The activity of PRMT5 is regulated at various levels involving interaction with regulatory proteins, PTM modifications and noncoding RNA. Several PRMT5 inhibitors have been developed and are undergoing clinical trials or are in the preclinical phases. The current review concerns the regulation, biological functions, and therapeutic approaches for targeting PRMT5 with a focus on its role in tumor immunity. Critically, PRMT5 regulates the expression of Tip60 which we have shown is needed for FOXP3 regulatory interactions with DNA.