3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a rare autosomal recessive genetic disorder that affects ketogenesis and l-leucine catabolism, which generally appears during the first year of life. Patients with HL deficiency have a reduced capacity to synthesize ketone bodies. The disease is caused by lethal mutations in the HL gene (HMGCL). To date, up to 30 variant alleles (28 mutations and 2 SNPs) in 93 patients have been reported, with a recognizable population-specific mutational spectrum. This disorder is frequent in Saudi Arabia and the Iberian Peninsula (Portugal and Spain), where two mutations (122G>A and 109G>A) have been identified in 87% and 94% of the cases, respectively. In most countries a few patients have a high level of allelic heterogeneity. The mutations are distributed along the gene sequences, although some clustering was observed in exon 2, conforming a possible hot spot. Recently, the crystal structures of the human and two bacterial HL have been published. These experimentally obtained structures confirmed the overall architecture, previously predicted by our group and others using bioinformatic approaches, which shows the (betaalpha)8-barrel structure of the enzyme. In addition, the crystals confirmed the presence of an additional COOH domain containing important structures and residues for enzyme functionality and oligomerization processes. Here, we review all HMGCL mis-sense mutations identified to date, and their implication in enzyme structure and function is discussed. We found that genotype-phenotype correlations are difficult to establish because the evolution of the disease seems more related to the causes of hypoglycaemia (fasting or acute illness) than to a particular genotype.