In light of the promising results achieved in AML and ALL by selective targeting of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A), two enzymes at the crossroad between polyamine metabolism and protein methylation, in this review we examine and discuss the role of polyamines in epigenetic regulation and other biological processes supporting leukemic cell survival, proliferation and differentiation, which provides the opportunity to discover additional polyamine-related targets and design novel therapeutic combinations. Here, PRMT5 is linked to acute myeloid leukemia.