Short chain fatty acids (SCFA) such as acetate, propionate, and butyrate play a pivotal role in maintaining host metabolic and immune homeostasis. These metabolites are considered hallmarks of a healthy gut ecosystem and have been linked to the protection against inflammatory and metabolic diseases. However, the exact mechanism by which SCFA exert their effects on tissues and organs is unknown. We therefore developed a LC-MS based method for measuring SCFA which we used to quantify SCFA in 20 mouse organs. We report SCFA concentrations to be most abundant in the gastrointestinal tract with changes in abundance between different tissues, sexes, genotypes, and diet. Furthermore, emerging evidence suggests that SCFA, particularly acetate, can also be used as an alternative nutrient source in cancer cells. This process is driven by the acetate metabolism enzyme acetyl-CoA synthetase 2 (ACSS2), which converts acetate into acetyl-CoA. There exists a closely related acetyl-CoA synthetase called ACSS1 whose role in cancer is largely unexplored. We therefore set out to distinguish the cancer-promoting roles of ACSS1 versus ACSS2 in breast cancer and acute myeloid leukemia (AML). We found that expression of ACSS1 drives acetate utilization and alters the levels of mitochondrial metabolites, while loss of ACSS1 suppresses acetate metabolism in breast cancer and AML cell lines. We also show that loss of ACSS1 decreases AML tumor burden in mice, highlighting ACSS1 as a potential therapeutic target in some cancer types. Building on these findings, we next investigated how dietary sources of acetate, particularly alcohol consumption, contribute to breast cancer and lung immunity. We found alcohol consumption increases lung metastases. Additionally, we found that the lungs of alcohol fed mice have decreased infiltration of myeloid cells that have altered expression of antigen presenting molecules, cytokines, and chemokines. These effects on immune cell function and behavior could be reversed by interfering with acetate signaling. This thesis highlights SCFA metabolism, systemic metabolite profiling, and cancer as a disease model, offering new frameworks for investigating the interplay between metabolism and the immune system.