Adaptation to metabolic needs and changing environments is a basic requirement of every living system. These adaptations can be very quick and mild or slower but more drastic. In any case, cells have to constantly monitor their metabolic state and requirements. In this article we review general concepts as well as recent advances on how metabolites can regulate metabolic fluxes. We discuss how cells sense metabolite levels and how changing metabolite levels regulate metabolic enzymes on different levels, from specific allosteric regulation to global transcriptional regulation. We thereby focus on local metabolite sensing in mammalian cells and show that several major discoveries have only very recently been made.