Genetic mapping and positional cloning of genetically complex traits in the laboratory rat (Rattus norvegicus) has recently led to the identification of various susceptibility genes in different rat models. Rat genetics has benefited from revolutionary advances in molecular biology, genetics, genomics and informatics and provide an unparalleled resource for molecular genetic investigation of mammalian physiopathology and its underlying complex genetic architecture. In this review, we will consider different strategies that are being used in the successful positional cloning of rat complex trait genes in the context of recent progress in rodent and human genetics.