Longevity is a fundamental and fascinating topic in contemporary biological studies. Many genes, signaling pathways, and transcription factors have been reported to affect lifespanLifespan from yeast to humans. Formaldehyde participates in epigenetic regulatory roles in the methylationMethylation and demethylationDemethylation of DNADNA, RNARNA, and histoneHistones and exerts various toxic effectsToxic effects from animals to humans at higher concentrations, while the effects of lower concentrations have rarely been reported. We used Drosophila as a model organism to study the effects of formaldehyde at various concentrations on longevity and found that different concentrations of formaldehyde played different roles in lifespanLifespan and stress resistance in Drosophila. Since knocking down the expression level of formaldehyde dehydrogenase (FDH)Formaldehyde dehydrogenase (FDH) in the neural system of Drosophila could also extend lifespanLifespan and increase stress resistance, it is a hopeful way to screen for the genes in the Drosophila neural system to study the probable molecular mechanisms of longevity. In this chapter, we reviewed the progress of lifespan studies in Drosophila and their relationship with formaldehyde, de/methylation and FDH and proposed the hypothesis that balanced levels of formaldehyde in epigenetics and FDH improve lifespan. Formaldehyde is involved in epigenetics through its participation in methylation and demethylationDemethylation, including its relationship with FDH, thereby improving lifespan within a narrow range of concentrations.