Coxiella burnetii is an obligate intracellular bacterial pathogen that directs biogenesis of a lysosome-like, parasitophorous vacuole in mammalian cells. We recently reported that C. burnetii inhibits apoptotic cell death in macrophages, presumably as a mechanism to sustain the host for completion of its lengthy infectious cycle. In the current study, we further investigated C. burnetii manipulation of host cell signaling and apoptosis by examining the effect of C. burnetii infection on activation of 15 host proteins involved in stress responses, cytokine production, and apoptosis. C. burnetii infection of THP-1 human macrophage-like cells caused increased levels of phosphorylated c-Jun, Hsp27, Jun N-terminal protein kinase, and p38 at 2 h postinfection (hpi), and this activation rapidly decreased to near basal levels by 24 hpi. The prosurvival kinases Akt and Erk1/2 (extracellular signal-regulated kinases 1 and 2) were also activated at 2 to 6 hpi; however, the phosphorylation of these proteins increased coincident with C. burnetii replication through at least 72 hpi. Sustained phosphorylation of Akt and Erk1/2 was abolished by treatment of infected cells with rifampin, indicating their activation is a C. burnetii-directed event requiring pathogen RNA synthesis. Moreover, pharmacological inhibition of Akt or Erk1/2 significantly decreased C. burnetii antiapoptotic activity. Collectively, these results indicate the importance of C. burnetii modulation of host signaling and demonstrate a critical role for Akt and Erk1/2 in successful intracellular parasitism and maintenance of host cell viability.