This review examines the relative bioefficacy of 2-hydroxy-4-(methylthio) butanoic acid (HMTBA) and DL-methionine (DL-Met) which includes chemical, metabolic, nutritional, and statistical aspects of its bioefficacy. The chemical, enzymatic and biological differences and similarities between these two products are explained and the evidence and reasons for HMTBA relative bioefficacy to DL-Met in monogastric animals are discussed. In addition, appropriate statistical methods for comparing the bioefficacy of these two products for successful use of each product are provided. HMTBA is an organic acid precursor of L-Met. The chemical structure differences between HMTBA and DL-Met leads to differences in how and where the two materials are absorbed, enzymatically converted to L-Met and used by the animal. Because of these differences, when the two compounds are supplemented into animal feeds in graded doses, they do not produce dose response curves of the same form due in part to differences in intake and metabolism at the extremes of the dose response curves. At deficient levels of the response curve, HMTBA fed animals may exhibit lower feed consumption and growth than DL-Met while at requirement levels they may have greater feed consumption and growth. This review provides biological evidence for why these differences in growth response occur and demonstrates that lower growth, whether for DL-Met or HMTBA, does not mean that either product is being converted to methionine inefficiently. Since the two products have different dose response curves, statistically valid methods are provided for unbiased determination of relative bioefficacy across tested dose ranges. Field nutritionists typically feed commercial doses of HMTBA or DL-Met at a total sulphur amino acid dietary level capable of achieving maximum performance. At these commercial levels, and based on the evidence, the full relative bioefficacy of HMTBA relative to DL-Met is discussed.