This chapter discusses the diagnosis of acute lymphoblastic leukemia (ALL). The diagnosis may not fit clinical findings, the clinical impression, or a referred diagnosis by another physician. Individual cases of acute leukemia may sit on the edge of World Health Organization guidelines, resulting in questions if not confusion regarding the correct diagnosis. The two most important factors that predict the favorable treatment response of a patient with ALL are cytogenetic and molecular genetic findings and early response to treatment. These are most conveniently followed by minimal residual disease studies that also pose additional questions, such as when the bone marrow of a patient in clinical remission has morphologically observable lymphoid-like blasts in the bone marrow. This chapter addresses some of these issues by way of case presentations.