Perturbations in metabolic processes are associated with diseases such as obesity, type 2 diabetes mellitus, certain infections and some cancers. A resurgence of interest in creatine biology is developing, with new insights into a diverse set of regulatory functions for creatine. This resurgence is primarily driven by technological advances in genetic engineering and metabolism as well as by the realization that this metabolite has key roles in cells beyond the muscle and brain. Herein, we highlight the latest advances in creatine biology in tissues and cell types that have historically received little attention in the field. In adipose tissue, creatine controls thermogenic respiration and loss of this metabolite impairs whole-body energy expenditure, leading to obesity. We also cover the various roles that creatine metabolism has in cancer cell survival and the function of the immune system. Renewed interest in this area has begun to showcase the therapeutic potential that lies in understanding how changes in creatine metabolism lead to metabolic disease.