The immune system must identify genuine threats and avoid reacting to harmless microbes because immune responses, while critical for organismal survival, can cause severe damage and use substantial energy resources. Models for immune response initiation have mostly focused on the direct sensing of microorganisms through pattern recognition receptors. Here, we summarize key features of the leading models of immune response initiation and identify issues they fail to solve individually, including how the immune system distinguishes between pathogens and commensals. We hypothesize and argue that surveillance of disruption to organismal homeostasis and core cellular activities is central to detecting and resolving relevant threats effectively, including infection. We propose that hosts use pattern recognition receptors to identify microorganisms and use sensing of homeostasis disruption to assess the level of threat they pose. We predict that both types of information can be integrated through molecular coincidence detectors (such as inflammasomes or others not yet discovered) and used to determine whether to initiate an immune response, its quality, and its magnitude. This conceptual framework may guide the identification of novel targets and therapeutic strategies to improve the progression and outcome of infection, cancer, autoimmunity, and chronic conditions in which inflammation plays a critical role.