Living organisms are composed of millions different kinds of molecules. Both hydrophilic and hydrophobic molecules make up cells and tissues. However, in healthy tissues, hydrophobic portions (hyppos) are seldom exposed on the surface of the biological molecules and supramolecular organization. Since the water-insoluble molecules could form non-productive and even toxic aggregates in aqueous body fluid, they have the potential to disturb homeostasis of living organisms. It looks like living organisms have expended metabolic energy to verify the water-solubility of biological molecules in extracellular spaces and within the cells. I suggest that the network of proteins and cells responsible for handling water-insoluble molecules can be understood in a unified model, “a hyppo-handling system (HHS)”. It appears to have evolved to detect, quench and remove water-insoluble molecules or molecular complexes that have exposed hyppos. The hyppos could become exposed on biological molecules in various ways, like through denaturation, chemical modification, and digestion by bacterial enzymes. When the quenching/removing system is not sufficient to hide or get rid of hyppos, the innate immune system could be activated to accelerate removal of hyppos. It might help us understand why many innate immune receptors are activated by damage-associated molecular patterns as well as pathogen-associated molecular patterns. The ancient HHS appears to have evolved into a well organized innate immune system in higher eukaryotes to maintain homeostasis when disturbed by water-insoluble molecules. Comprehension of this process could broaden our understanding of various immune-mediated pathogenesis by infection, autoimmunity, allergies, atherosclerosis, diabetes and neurodegenerative disease like Alzheimers disease.