During the past 20 yr, molecular biology and molecular genetics have provided techniques and procedures that allow the precise diagnoses of leukemias and lymphomas (for a review, see ref. 1). These methodologies have provided powerful, robust, and precise characterizations of genetic mutations and gene rearrangements (both normal and abnormal) that have been applied to the diagnosis and treatment of these malignancies. In this chapter we discuss methodologies currently utilized within the molecular diagnostic laboratory of cancer centers and major academic hospitals. We introduce these methodologies in both general terms and within the context of a differential diagnosis of leukemia/lymphoma. The long-term goal of the molecular hematologist/oncologist is to describe all mutations that occur within a given type or subtype of leukemia/lymphoma. This involves the discovery of new somatic and possibly hereditary mutations that contribute to the genesis of these hematologic malignancies. However, for this information to be useful in treatment regimens, therapies that target or affect these growth-dysregulating mutations must be found. Because diagnosis of mutation and gene rearrangement in the hematologic malignancies is far ahead of therapeutic modalities, we also discuss new research tools that will have impact on the experimental hematologist.