Toxoplasma gondii is an obligate intracellular parasite that can infect all warm-blooded animals, including an estimated ~30% of humans. It can cause severe disease in immune-suppressed individuals and in fetuses as well as blinding chorioretinitis in adults and children. Toxoplasma-innate immune system interactions determine early parasite control and activation of the adaptive immune system by the host and are therefore critical in determining host survival during the acute phase of infection. However, induction of an exaggerated inflammatory response can also lead to pathology. Only the chronic tissue cyst form of Toxoplasma is orally infectious. It is therefore critical for the parasite’s survival during the chronic phase to escape immune responses at this stage as well. Toxoplasma exists as genetically divergent strains mostly depending on geography, with the most strain diversity being found in South America. The key to Toxoplasma’s successful co-option of the host are proteins secreted from its rhoptry and dense granule secretory organelles. Rhoptry proteins (ROPs) are secreted into the host cell cytoplasm upon invasion while dense granule proteins (GRAs) are secreted once the parasite establishes itself in its parasitophorous vacuole (PV). GRAs can localize to the PV, the PV membrane, or are secreted beyond the PVM into the host cytoplasm. Many ROPs and GRAs are involved in modulating host cell signaling pathways and evasion of host immune responses and play important roles in Toxoplasma virulence. Polymorphisms in Toxoplasma’s ROPs and GRAs, likely determine how well these effectors bind to the divergent substrates in different host species, which can explain Toxoplasma strain differences in virulence in a particular host species. By studying Toxoplasma we have not only started to unravel how the parasite modulates immune responses to enhance its survival, replication, and transmission but we have also learned a lot about the immune system. Many unique mechanisms of immunity have indeed been defined using Toxoplasma and this parasite has aided our understanding of tissue-specific immune responses in the brain and intestine. This Research Topic will give a comprehensive overview of Toxoplasma-host immune response interactions. Most Toxoplasma virulence determinants to date have been established in murine systems and it is unclear how the parasite interacts with other intermediate hosts and humans. In addition, the interactions of Toxoplasma with some of the most relevant cell types during infection, including dendritic cells, neurons, intestinal epithelial cells or vascular endothelial cells, remain poorly understood.