5-hydroxymethylcytosine (5hmC) is a major oxidation product of 5-methylcytosine (5mC) catalyzed by ten-eleven translocation (TET) enzymes. Recent studies have revealed that 5hmC is not only an intermediate of active DNA demethylation, but also a stable epigenetic marker that could act as a bridge between environmental exposure and disease outcomes. Exposure to environmental factors can regulate the occurrence and development of diseases by affecting the pattern of genomic 5hmC, while 5hmC may be more sensitive than 5mC in reflecting the health effects caused by exposure to some external environmental factors. Therefore, it is critical to uncover the roles of 5hmC in the associations between environmental exposure and disease outcomes, in order to clarify the underlying mechanisms of the occurrence and development of diseases, develop early diagnostic techniques, and identify effective intervention targets. In the present study, we reviewed the published literature reporting the effects of environmental factors on 5hmC, as well as the associations between 5hmC and chronic diseases.