Phosphomannomutase (PMM2, Mannose-6-P--> Mannose-1-P) deficiency is the most frequent glycosylation disorder affecting the N-glycosylation pathway. There is no therapy for the hundreds of patients who suffer from this disorder. This review describes previous attempts at therapeutic interventions and introduces perspectives emerging from the drawing boards. Two approaches aim to increase Mannose-1-P: small membrane permeable molecules that increase the availability or/and metabolic flux of precursors into the impaired glycosylation pathway; and, phosphomannomutase enhancement and/or replacement therapy. Glycosylation-deficient cell and animal models are needed to determine which individual or combined approaches improve glycosylation and may be suitable for preclinical evaluation.