Hematopoietic stem cells (HSC) and T cells are intimately related, lineage-dependent cell populations that are extensively used as therapeutic products for the treatment of hematologic malignancies and certain types of solid tumors. These cellular therapies can be life-saving treatments; however, their efficacies are often limited by factors influencing their activity and cellular properties. Among these factors is mitochondrial metabolism, which influences the function and fate commitment of both HSCs and T cells. Mitochondria, besides being the "cellular powerhouse," provide metabolic intermediates that are used as substrates for epigenetic modifications and chromatin remodeling, thus, driving cell fate decisions during differentiation. Moreover, mitochondrial fitness and mitochondrial quality control mechanisms are closely related to cellular function, and impairment of these mitochondrial properties associates with cellular dysfunction due to factors such as T-cell exhaustion and aging. Here, we give an overview of the role of mitochondria in shaping the behavior of these lineage-related cell populations. Moreover, we discuss the potential of novel mitochondria-targeting strategies for enhancing HSC- and T cell-based cancer immunotherapies and highlight how design and application of such approaches requires consideration of the metabolic similarities and differences between HSCs and T cells. See related article on p. 1302.