Tissue-, sex-, and age-specific epigenetic modifications such as DNA methylation are largely unknown. Changes in DNA methylation of the glucocorticoid receptor gene () and imprinting control region (ICR) of and genes during the lifespan are particularly interesting since these genes are susceptible to epigenetic modifications by prenatal stress or malnutrition. They are important regulators of development and aging. Methylation changes of affect glucocorticoid receptor expression, which is associated with stress sensitivity and stress-related diseases predominantly occurring during aging. Methylation changes of affect growth trajectory and nutrient use with risk of metabolic syndrome. Using a locus-specific approach, we characterized DNA methylation patterns of different promoters and ICR in seven tissues of rats at 3, 9, and 24 mo of age. We found a complex pattern of locus-, tissue-, sex-, and age-specific DNA methylation. Tissue-specific methylation was most prominent at the shores of the CpG island (CGI). Sex-specific differences in methylation peaked at 9 mo. During aging, predominantly displayed hypomethylation mainly in females and at shores, whereas hypermethylation occurred within the CGI. ICR exhibited age-related hypomethylation occurring mainly in males. Methylation patterns of in the skin correlated with those in the cortex, hippocampus, and hypothalamus. Skin may serve as proxy for methylation changes in central parts of the hypothalamic-pituitary-adrenal axis and hence for vulnerability to stress- and age-associated diseases. Thus, we provide in-depth insight into the complex DNA methylation changes of rat and during aging that are tissue and sex specific.