Current induction therapies for acute and chronic leukemias and the lymphomas have achieved significant complete remission rates. Despite this initial success, disease recurrence remains a major problem. Relapse from clinically undetectable residual malignant cells is the most likely mechanism of recurrence. Of crucial importance to the clinician is the accurate detection of residual malignant cells prior to clinical relapse. Standard approaches to evaluate for this minimal residual disease (MRD) allow detection only when the malignant clone exceeds 1%. Patients in remission, however, may frequently have residual neoplastic cells that are far below this level. Recently, several investigators have adapted the polymerase chain reaction (PCR) to detect tumor-specific DNA or RNA sequences. This approach is highly sensitive (able to detect 1 malignant cell in 10(6) normal cells). The application of this technique to the study of MRD thus far has been limited to tumors in which specific DNA or RNA sequence data are available. This review describes the application of PCR to the detection of MRD in patients with chronic myelogenous leukemia, acute lymphoblastic leukemia, and follicular small cleaved cell lymphoma. Because the number of clinical studies and length of follow-up is limited, detection of MRD by PCR is at present largely a research tool and the biological significance of MRD as determined by PCR must await further studies.