Molecular dissection of physiologic and pathologic genetic phenomena in hematologic malignancy has provided the pathologist with a broad menu of new assays. By integrating the data gleaned from these techniques we can formulate more rational and biologically based diagnoses, which should lead to the ultimate goal of targeted therapy for these specific entities. We summarize some of the more relevant molecular genetic assays and present an overview of those genetic mechanisms usually evaluated in the current practice of hematopathology. The usefulness of such assays extends beyond refining diagnoses in that they also provide relevant prognostic information. Moreover, since most are based on the polymerase chain reaction and reverse transcriptase polymerase chain reaction, we are more sensitively able to monitor for residual disease after attempts at curative therapy, and our definition of remission has been dramatically altered. However, molecular genetic tests are not without limitations, and we must remain cognizant of their cost effectiveness and be aware of current deficiencies in standardization. The challenge will be to meaningfully and economically harness and integrate the information we obtain from these and future technologies into appropriate clinical practice.