Aging and environmental exposures alter tissue-specific DNA methylation depending on CpG island context. This study analyzed 217 normal human tissues from 10 anatomic sites at 1,413 CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and how aging and exposures contribute to normal methylation variation. Methylation profile classes derived from unsupervised modeling were significantly associated with age and were significant predictors of tissue origin. In solid tissues, CpG island-dependent correlations between age and methylation were striking, with loci in CpG islands gaining methylation with age and loci not in CpG islands losing methylation with age. These patterns were consistent across tissues and in blood-derived DNA. The study demonstrates age- and exposure-related differences in tissue-specific methylation and significant age-associated methylation patterns that are CpG island context-dependent. This work provides new insights into the role of aging and the environment in disease susceptibility, particularly cancer, and informs epigenomics by showing evidence of epigenetic dysregulation due to age-related methylation changes. The study reveals key issues to consider in constructing reference and disease-related epigenomes and interpreting potentially pathologically important alterations. It also highlights the dynamic nature of epigenomes and begins to disentangle the roles of aging, environmental factors, and innate variability in epigenomic profiles. The study used Illumina's GoldenGate methylation platform to investigate cytosine methylation in 217 normal human tissue specimens to understand variation between and within tissues. Results showed that methylation profiles were significantly associated with age and environmental exposures. The study also found that age-related methylation alterations were CpG island context-dependent, with CpG island loci showing increased methylation with age and non-island loci showing decreased methylation. The study confirmed these findings using pyrosequencing and showed that age-related methylation alterations were tissue-specific and influenced by environmental exposures. The study provides a novel path for examining the mechanistic basis of these alterations and highlights the importance of considering CpG island context in understanding age-related methylation changes. The study also emphasizes the need for further research to define the mechanisms controlling epigenomic variation and to identify the most critical alterations in specific diseases. The study's findings have important implications for understanding the relationship between aging, environmental exposures, and epigenetic changes in disease susceptibility.Aging and environmental exposures alter tissue-specific DNA methylation depending on CpG island context. This study analyzed 217 normal human tissues from 10 anatomic sites at 1,413 CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and how aging and exposures contribute to normal methylation variation. Methylation profile classes derived from unsupervised modeling were significantly associated with age and were significant predictors of tissue origin. In solid tissues, CpG island-dependent correlations between age and methylation were striking, with loci in CpG islands gaining methylation with age and loci not in CpG islands losing methylation with age. These patterns were consistent across tissues and in blood-derived DNA. The study demonstrates age- and exposure-related differences in tissue-specific methylation and significant age-associated methylation patterns that are CpG island context-dependent. This work provides new insights into the role of aging and the environment in disease susceptibility, particularly cancer, and informs epigenomics by showing evidence of epigenetic dysregulation due to age-related methylation changes. The study reveals key issues to consider in constructing reference and disease-related epigenomes and interpreting potentially pathologically important alterations. It also highlights the dynamic nature of epigenomes and begins to disentangle the roles of aging, environmental factors, and innate variability in epigenomic profiles. The study used Illumina's GoldenGate methylation platform to investigate cytosine methylation in 217 normal human tissue specimens to understand variation between and within tissues. Results showed that methylation profiles were significantly associated with age and environmental exposures. The study also found that age-related methylation alterations were CpG island context-dependent, with CpG island loci showing increased methylation with age and non-island loci showing decreased methylation. The study confirmed these findings using pyrosequencing and showed that age-related methylation alterations were tissue-specific and influenced by environmental exposures. The study provides a novel path for examining the mechanistic basis of these alterations and highlights the importance of considering CpG island context in understanding age-related methylation changes. The study also emphasizes the need for further research to define the mechanisms controlling epigenomic variation and to identify the most critical alterations in specific diseases. The study's findings have important implications for understanding the relationship between aging, environmental exposures, and epigenetic changes in disease susceptibility.