Mannose metabolism: More than meets the eye

•Mammalian plasma contains 50–100μM mannose and dietary mannose supplements raise it 3–5-fold.•Mutations in mannose-metabolizing enzymes cause Congenital Disorders of Glycosylation (CDG).•Mannose supplements treat phosphomannose isomerase (MPI) deficient CDG patients.•Mannose supplements kill Mpi-hypomorphic mouse embryos and blind survivors.•Mannose is a routine remedy for urinary tract infections. Caution, especially during pregnancy. Mannose is a simple sugar with a complex life. It is a welcome therapy for genetic and acquired human diseases, but it kills honeybees and blinds baby mice. It could cause diabetic complications. Mannose chemistry, metabolism, and metabolomics in cells, tissues and mammals can help explain these multiple systemic effects. Mannose has good, bad or ugly outcomes depending on its steady state levels and metabolic flux. This review describes the role of mannose at cellular level and its impact on organisms.