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Vitamin B12 deficiency is common in certain populations, such as in India, where there is also a rising prevalence of Type 2 diabetes, obesity and their complications. Human cohorts and animal models provide compelling data suggesting the role of the one-carbon cycle in modulating the risk of diabetes and adiposity via developmental programming. Early mechanistic studies in animals suggest that alterations to the cellular provision of methyl groups (via the one-carbon cycle) in early developmental life may disrupt DNA methylation and induce future adverse phenotypic changes. Furthermore, replacement of micronutrient deficits at suitable developmental stages may modulate this risk. Current human studies are limited by a range of factors, including the accuracy and availability of methods to measure nutritional components in the one-carbon cycle, and whether its disruptions exert tissue-specific effects. A greater understanding of the causal and mechanistic role of the one-carbon cycle is hoped to generate substantial insights into its role in the developmental origins of complex metabolic diseases and the potential of targeted and population-wide prevention strategies.