Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.