Megaloblastic anemia can be due to cobalamin deficiency, folate deficiency, or refractory forms of bone marrow disease. This essay reviews current thinking on the diagnostic procedures available to a physician considering these disorders. The questions to be answered are as follows: Is a megaloblastic anemia present? Is there a deficiency of cobalamin or folate? If a deficiency is present, what is its cause? Various diagnostic tests are discussed with regard to the differences in their sensitivity and metabolic implications. In particular, we consider the newest diagnostic tests for cobalamin deficiency, serum homocysteine, and methylmalonate, which appear to be highly sensitive predictors of clinical morbidity. Application of these tests suggests that many more patients are cobalamin-deficient than had been supposed.