Although cobalamin (vitamin B<sub>12</sub>) deficiency was described over a century ago, it is still difficult to establish the correct diagnosis and prescribe the right treatment. Symptoms related to vitamin B<sub>12</sub> deficiency may be diverse and vary from neurologic to psychiatric. A number of individuals with vitamin B<sub>12</sub> deficiency may present with the classic megaloblastic anemia. In clinical practice, many cases of vitamin B<sub>12</sub> deficiency are overlooked or sometimes even misdiagnosed. In this review, we describe the heterogeneous disease spectrum of patients with vitamin B<sub>12</sub> deficiency in whom the diagnosis was either based on low serum B<sub>12</sub> levels, elevated biomarkers like methylmalonic acid and/or homocysteine, or the improvement of clinical symptoms after the institution of parenteral vitamin B<sub>12</sub> therapy. We discuss the possible clinical signs and symptoms of patients with B<sub>12</sub> deficiency and the various pitfalls of diagnosis and treatment.