Molecular diagnostics in low grade B cell lymphoma is currently based on polymerase chain reaction (PCR) detection of lymphoid clonality or of molecular (onco)genetic markers that result from chromosomal translocations. The former is based on detection of clonal immunoglobulin (Ig) and/or T cell receptor (TCR) rearrangements, which can be used for distinguishing between malignant and reactive lymphoproliferation, for staging, for comparison of diagnostic and relapse material and for minimal residual disease assessment. Informativity has risen with the development of improved, standardised DNA-based Ig/TCR strategies but remains dependent on tumour subtype, largely as a function of the rate of IgH somatic mutation. PCR-based detection of molecular genetic markers can aid diagnosis, although genetic breakpoint heterogeneity and low level molecular informativity means that alternative techniques, such as fluorescent in situ hybridisation or immunohistochemistry of the deregulated genes, can be preferable. Appropriate molecular diagnostic practise is entirely dependent on the conservation of appropriate material, with the increasing tendency for RNA based diagnostics, particularly for transcriptional profiling, rendering tissue banking of unfixed material extremely important. Therapeutic stratification of patients with low grade lymphoma is likely to be increasingly based on multiparameter genetic and/or immunological analysis, with monoparameter targets being reserved for follow-up. Appropriate use of the increasing number of analytical techniques available is best applied in specialised diagnostic platforms with a complementary, interdisciplinary approach that can be adapted to the clinical situation.