To advance our knowledge of MondoA/ChREBP, this review will summarize the recent findings concerning the respective regulation and functions of MondoA and ChREBP in each metabolic organ (i.e., the skeletal muscle, liver, adipose tissue, and pancreas), with an emphasis on its challenges and opportunities in the treatment of T2D. This evidence concerns the gene MLXIPL and type 2 diabetes mellitus.