Tissue-resident memory T cells (T_RM) persist in peripheral tissues for long periods of time in the absence of antigenic stimulation. Upon re-encounter with cognate antigen, T_RM trigger an immediate immune response at the local tissue microenvironment and provide the first line of host defense. T_RM have been reported to play significant roles in host antimicrobial infection, cancer immunotherapy, and pathogenesis of a number of human autoimmune diseases, such as psoriasis, vitiligo, and atopic dermatitis. T_RM display a distinct gene transcriptome with unique gene expression profiles related to cellular metabolism that is different from naive T cells (T_N), central memory T cells (T_CM), and effector memory T cells (T_EM). Skin CD8⁺ T_RM upregulate expression of genes associated with lipid uptake and metabolism and utilize mitochondria fatty acid β-oxidation to support their long-term survival (longevity) and function. In this review, we will summarize the recent progresses in the metabolic programming of T_RM and will also discuss the potential to target the unique metabolic pathways of T_RM to treat T_RM-mediated diseases.