<p>Stem cells maintain tissue architecture by replacing differentiated cells at steady state and upon injury. Implementing this cornerstone role requires protection of stem cells from pathogens and from the toxic effects of immune system activation. However, the pro-inflammatory innate immune mechanisms that protect differentiated cells from infection are poorly functional in stem cells. Instead, stem cells employ other specific defence mechanisms, such as antiviral RNA interference. At steady state, the proliferation and differentiation of tissue stem cells is regulated by multiple cell types, including immune cells. Following sterile tissue injury or during infection, the immune response — in addition to controlling pathogens and clearing cell debris — orchestrates tissue repair by fine-tuning stem cell activity, through direct cell–cell contacts and via inflammatory mediators such as cytokines. There is thus stem–immune cross-talk that is fundamental to the maintenance of tissue homeostasis. Inflammageing, which is defined as the age-driven elevation of inflammation and is associated with an altered immune cell composition, profoundly affects this stem–immune cross-talk, impacting the ability to repair tissues and participating in ageing of the whole organism.</p>