Human genetic disease is known to result from both point mutations and chromosomal aberrations. It is therefore critical that short-term in vitro mammalian tests be evaluated as to their capabilities for detecting both types of lesions. Research to date indicates that L5178Y/TK plus or minus -3.7.2C mouse lymphoma cells permit the measurement of forward mutation at the heterozygous tk locus. Extensive studies indicate that these TK-deficient mutants result from both single-gene mutations (small-colony mutants) as well as mutations involving the expression of multiple loci (large-colony mutants). Comparative mutagenicity studies presented at this Banbury conference reveal a quantitative difference in the ability of the tk and hgprt loci to permit recovery of mutations affecting the expression of multiple loci. The observed HGPRT mutant frequency underestimates the genotoxicity of compounds acting as clastogens.