Toxoplasma gondii is an obligate intracellular parasite that can infect any nucleated cell in any tissue of warm-blooded animals. How does the parasite have such a wide host cell and tissue tropism? One mechanism is by the parasite expressing its own host cell receptor complex that it injects into the host cell. But as the parasite disseminates through its host, it encounters diverse environments that it that it must adapt to so that it can replicate, grow, and cause disease. Oxygen is one environmental factor whose levels change dramatically in tissues and all cells must detect and respond to changes in oxygen availability. Prolyl hydroxylases are dioxygenases that function as key cellular oxygen sensing proteins. In mammals, the transcription factor Hypoxia-Inducible Factor-1a is the best recognized prolyl hydroxylase substrate and our earlier work revealed that parasite growth at low oxygen requires HIF-1 activation. These studies led us to study how Toxoplasma itself senses oxygen? To address this question, we used BLAST analysis and identified 2 Toxoplasma-encoded prolyl hydroxylase homologs that we named PHYa and PHYb. PHYa prolyl hydroxylates SKP1, which is an adaptor in the Skp1/Cullin-1/F-box protein (SCF)-E3 ubiquitin ligase complex. SKP1 prolyl hydroxylation alters its binding preferences for F-Box proteins leading to changes in which proteins are ubiquitinated by the SCF-E3. PHYa is required for growth at low oxygen and is required for virulence as it is critically required to resist IFNγ-dependent killing. PHYb, on the other hand, is required for growth and survival of parasites exposed to stress at elevated oxygen levels and does so by inhibiting phosphorylation of elongation factor 2 (eEF2). eEF2 phosphorylation inhibits it from catalyzing the translocation of the peptidyl-tRNA complex from the A-site to the P-site of the ribosome. We have shown that PHYb promotes protein synthesis to ensure that the parasite proteins are available to ensure that the stress response is properly executed. In this talk, we will discuss new data regarding how PHYa and PHYb function. Taken together, these data indicate that the two prolyl hydroxylases work together as an oxygen sensing rheostat in regulating protein synthesis and degradation to ensure that the parasite proteome is programmed to enable Toxoplasma to grow, survive, and cause disease at whatever oxygen tension it faces.