NATURE REVIEWS | GENETICS VOLUME 6 | APRIL 2005 | 271 REVIEWS In the 1990s, when it first became possible to map the chromosomal locations of quantitative trait loci (QTLs) in rodents, it looked as if QTL discovery would soon lead to the identification of genes involved in any med- ically important phenotype that could be modelled in mice or rats 1–4 . More than 10 years later, the field of QTL analysis is heading towards a crisis. The National Center for Biotechnology Information (NCBI) lists 700 QTLs that are found in rats (see the Entrez Gene web site in the Online links box), and the mouse genome database cur- rently contains 2,050 mouse QTLs (see the Mouse Genome Informatics web site in the Online links box). Compare these figures with the number of candidate genes that are proposed to underlie QTLs in rodents (TABLES 1,2). If we uncritically accept all the claims as cor- rect, only about 20 genes have been identified. Even if no more QTLs are mapped, at the present rate of progress (20 genes identified in 15 years) it will take 1,500 years to find all the genes that underlie known QTLs. Several recent developments have been published that might make what is currently almost impossible more tractable. These include new genomic resources (for example, the availability of sequences and sequence variants), animal resources (for example, chromosome substitution strains and the proposed Collaborative Cross), techniques (such as in silico mapping and whole-genome expression studies) and analytical tools (such as quantitative complementa- tion tests and Yin–Yang crosses, see below for more information). In this review, we discuss the realized or potential success of new approaches to identify genes that under- lie QTLs.We focus on methods to identify genetic vari- ants that have only a small effect on the phenotype (by which we mean that the variants account for 10% or less of the phenotypic variation of a quantitative trait). In the past, robust and reliable detection of small-effect QTLs has been a problem 5 ; but, as should be evident from the number of QTLs that have been reported, difficulties in QTL detection are not imped- ing research. The methods might not be the most effi- cient, but there is no doubt that QTLs can be detected at high levels of significance and that the findings can be replicated, even for behavioural phenotypes 6–9 . Although it is likely that only a small fraction of the total number of QTLs that segregate in inbred strain crosses are currently known to us (not to mention those in outbred stocks), without the ability to deter- mine the genes they represent, their detection is of limited interest. We urgently need advances in gene, not QTL, identification. STRATEGIES FOR MAPPING AND CLONING QUANTITATIVE TRAIT GENES IN RODENTS Jonathan Flint, William Valdar, Sagiv Shifman and Richard Mott Abstract | Over the past 15 years, more than 2,000 quantitative trait loci (QTLs) have been identified in crosses between inbred strains of mice and rats, but less than 1% have been characterized at a molecular level. However, new resources, such as chromosome substitution strains and the proposed Collaborative Cross, together with new analytical tools, including probabilistic ancestral haplotype reconstruction in outbred mice, Yin–Yang crosses and in silico analysis of sequence variants in many inbred strains, could make QTL cloning tractable. We review the potential of these strategies to identify genes that underlie QTLs in rodents. Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, United Kingdom. Correspondence to J.F. e-mail: jf@well.ox.ac.uk doi:10.1038/nrg1576 © 2005 Nature Publishing Group