For over seven decades, Coxiella burnetii, the causative agent of human Q fever, has been considered a prototypical obligate intracellular bacterium that relies exclusively on a eukaryotic cell for growth. Intracellularly, the organism prospers in an acidified, phagolysosome-like vacuole. C. burnetii has evolved to replicate in this harsh compartment by a mechanism involving acid activation of metabolism. The ?2 Mb genome of C. burnetii is about twice the size of genomes of most obligate intracellular bacteria, and the organism's central metabolic pathways are largely intact. The absence of extensive genome reduction suggests the adaptation of C. burnetii to an obligate intracellular lifestyle is a recent evolutionary event. Indeed, insight from early work on C. burnetii metabolism, along with new information gained from metabolic pathway reconstructions, nutrient typing, and expression profiling, allowed the rescue of C. burnetii from its host cell to regain the axenic growth capacity of its ancestors. This advance removes the extensive experimental obstacles associated with intracellular obligatism and opens the door for a renaissance in C. burnetii research.