A property of susceptibility genes for complex diseases is their reduced penetrance, due to the influences of other genes, the environment, or stochastic events. With this in mind, it is possible to devise population genetic strategies and statistical methods to allow their positional cloning. The identification of the relevant effector gene in an implicated locus may provide further challenges and require functional studies. The challenges of positional cloning are demonstrated by two examples: the cloning of GPRA and AAA1 on chromosome 7p14 at a susceptibility locus for asthma and atopy, and the study of HCR on chromosome 6p21 at PSORS1, the major susceptibility locus for psoriasis. To implicate GPRA in asthma and atopy, we studied its isoform-specific expression in bronchial biopsies and other sites for allergic reactions. We also studied its expression in a mouse model of ovalbumin-induced hypersensitivity. To study the role of HCR in psoriasis, we engineered transgenic mice with either a HCR non-risk allele or the HCR *WWCC risk allele controlled by the cytokeratin 14 promoter. The results suggested that while the overexpression of HCR in mouse skin is insufficient to induce a psoriasiform phenotype, it appears to induce allele-specific gene expression changes similar to those in psoriatic skin.