Leukemias are a class of human cancers that originate from hematopoietic progenitors and are characterized by extensive remodeling of the immune microenvironment. Leukemic cells, on transformation, acquire the ability to evade immune recognition but, despite undergoing genetic and epigenetic changes, retain their characteristic immature immune signature. For this and other reasons, leukemias are often refractory to immune therapies. In the present Review, we cover these areas as a means of improving outcomes from a deeper understanding of immune rewiring, inflammatory signaling and the barriers to successful implementation of immune therapies.