Inflammation is part of the body’s defense against any stimuli, which is defined as harmful by the immune system. Acute inflammation is composed of an initial attacking phase where cells and tissues in the targeted region is destroyed, followed by a healing process. Chronic inflammation occurs when the immune system is constantly actvated, as the cause of the activation cannot be destroyed. Many common diseases have been related to chronic inflammation, including dementia, rheumatic diseases, MS etc., as well as cancer and many diseases of the vascular system. Despite the enormous global research effort there is an incomplete understanding of the molecular mechanisms that initiates inflammation. This is partly due to the complexity of the common diseases, where a plethora of different factors and pathways can be involved in the inflammation process. As a contrast, the monogenic autoinflammatory diseases represent a unique opportunity to characterize inflammatory pathways resulting from a single factor, from its initiation to the resulting clinical phenotypes. Three monogenic autoinflammatory diseases, alpha-mannosidosis, DADA2, and DNase 2 deficiency, will be presented. For each of these diseases defined metabolites (glycans and DNA) accumulate in the lysosomes of macrophages. The only way to reconcile the observed phenotypes with the respective deficiencies is a leakage of small metabolites from the lysosomes to cytosol, where the binding to cytosolic receptors initiates an inflammation cascade. The impact of this model on our understanding of common diseases will be discussed.