Dysmetabolism of formaldehyde shows a positive relationship with age-related cognitive impairment for approximately 30–40% of Alzheimer’s disease (AD) patients who have high levels of urine formaldehyde (see Chap. 9 ). To have a clear explanation, we divide the cellular formaldehyde pathways into two parts: “formaldehyde coming (synthesis or production)” and “formaldehyde going (process or degradation).” The metabolic homeostasis of formaldehyde is maintained between the “coming” and “going” pathways under the physiological state. In fact, formaldehyde comes from multiple pathways related to many compounds, such as sugars, lipids, amino acids, proteins, and nucleic acids, as well as some small molecules, and goes away in a relatively narrow metabolic lane. In addition, it also participates in other pathways, for instance, as a donor to modify histones, RNA, and DNA. Either “coming” or “going” metabolism dysfunctions would lead to an increase or decrease in endogenous formaldehyde. As described in Chap. 8 , an imbalance (lack or excess) in formaldehyde metabolism induces a decline in learning and memory in Drosophila and rodents. It is known that the intestinal microbiota is involved in the metabolism of endogenous formaldehyde, and we discuss this topic in detail in Chap. 7 . In this section, we discuss the characteristics of endogenous formaldehyde metabolism and summarize the pathways that are responsible for the generation and clearance of endogenous formaldehyde. To prevent excess formaldehyde accumulation, effective strategies, including modulators and medical devices that could target enzymes during the metabolism of formaldehyde, are also reviewed.