Because it reaches full functional efficacy rapidly upon encounter with a pathogen, the innate immune system is considered as the first line of defense against infections. The sensing of microbes or of transformed or infected cells, through innate immune recognition receptors (referred to as activating I2R2), initiates pro-inflammatory responses and innate immune effector functions. Other I2R2 with inhibitory properties bind self-ligands constitutively expressed in host. However, this dichotomy in the recognition of foreign or induced self versus constitutive self by I2R2 is not always respected in certain non-infectious conditions reminiscent of immunopathologies. In this review, we discuss that immune mechanisms have evolved to avoid inappropriate inflammatory disorders in individuals. Molecular crossregulation exists between components of I2R2 signaling pathways, and intricate interactions between cells from both innate and adaptive immune systems set the bases of controlled immune responses. We also pinpoint that, like T or B cells, some cells of the innate immune system must go through education processes to prevent autoreactivity. In addition, we illustrate how gene expression profiling of immune cell types is a useful tool to find functional homologies between cell subsets of different species and to speculate about unidentified functions of these cells in the responses to pathogen infections.