Summary: Two-signal models have a rich history in immunology. In the classic two-signal model of T-cell activation, signal one consists of engagement of the T-cell receptor by antigen/major histocompatibility complex, whereas signal two arises from costimulatory ligands on antigen-presenting cells. A requirement for two independent signals helps to ensure that T-cell responses are initiated only in response to bona fide infectious threats. Our studies have led us to conclude that initiation of innate immune responses to pathogens also often requires two signals: signal one is initiated by a microbe-derived ligand, such as lipopolysaccharide (LPS) or flagellin, whereas signal two conveys additional contextual information that often accompanies infectious microbes. Although signal one alone is sufficient to initiate many innate responses, certain responses—particularly ones with the potential for self-damage—require two signals for activation. Many of our studies have employed the intracellular bacterial pathogen Legionella pneumophila, which has been established as a valuable model for understanding innate immune responses. In this review, we discuss how the innate immune system integrates multiple signals to generate an effective response to L. pneumophila and other bacterial pathogens.