The chromosomal translocation t(14;18)(q32;q21) is characteristic of follicular lymphoma and a frequent abnormality in other types of non-Hodgkin lymphoma (NHL). In healthy individuals, the same translocation may also be found in a small fraction of peripheral blood lymphocytes, the biological significance of which is beginning to be explored. Translocation prevalence and frequency are potential risk factors for developing NHL. Here, we review the published data and describe recent and ongoing work on this promising biomarker. We have a series of studies in four major areas: 1) t(14;18) prevalence and frequency in healthy individuals; 2) maturation of translocation-harboring cells; 3) effect of rituximab treatment on t(14;18) carriage; and 4) predictive and clonotypic relationship between t(14;18) and follicular lymphoma or other NHL. Further studies are warranted to increase understanding of this crucial molecular event in the development of hematopoietic malignancies. Potential applications include determination of elevated risk for lymphoma, early detection of disease, and identification of molecular targets for preventive interventions.