Cell surface expression through attachment to glycosylphosphatidylinositol (GPI) is a mode of protein expression highly conserved in eukaryotes. GPI-anchored proteins (GPI-AP) serve a variety of functions that include adhesion, receptors, signal transduction, and complement activation. Paroxysmal nocturnal hemoglobinuria, a rare acquired disorder of hematopoiesis caused by somatic mutations in the X-linked PIG-A gene, was until recently the only genetic disorder affecting GPI biosynthesis. The strict requirement for intact GPI biosynthesis during embryonic and fetal development accounted for the paucity of reported cases of inherited forms of GPI deficiency. Here, we review the clinical spectrum, biochemical defect, and genetic pathogenesis of the first cases of inherited GPI deficiency (IGD), an autosomal recessive disorder caused by a hypomorphic mutation in the promoter of PIG-M, a gene which like PIG-A, is indispensable for GPI biosynthesis. Further, we discuss the evidence suggesting that IGD is a disorder of gene-specific histone hypoacetylation and that pharmacological manipulation targeted to histone acetylation is of therapeutic benefit in IGD.