Organelles extensively communicate with each other to regulate cellular responses. The aim of the present study was to reveal the involvement of organelle communication in regulation of host defense responses. In particular, we focused on the functions and roles of organelle communication in regulation of innate immune response. The innate immune system senses pathogens and induces the release of inflammatory mediators leading to the induction of host defense responses. However, the innate immune system often induces an aberrant inflammatory response, which causes severe tissue damage. Therefore, understanding the mechanisms underlying the regulation of innate immune system is required for identifying promising targets for developing anti-inflammatory drugs. We observed that communication among organelles such as lysosomes and mitochondria was involved in the regulation of innate immune response. We also observed that compounds targeting organelle communication-mediated innate immune response blocked inflammation-induced tissue damage. Here, we will discuss the spatial regulation of innate immune response and anti-inflammatory effects of compounds targeting it from the perspective of organelle communication.