Yellow fever (YF) is the major public health problem for hundreds of millions of people in large parts of tropical Africa and South America, and millions of travelers to endemic areas are also at risk of exposure and infection. There is no effective drug treatment, resulting in a dramatic increase in the number of YF cases, being YF considered as a reemerging disease. The infection may be prevented by vaccinating human populations at risk for exposure. Nowadays, two live, attenuated YF vaccines are in use: 17D-204 and 17DD. Although fatal adverse events experienced by the vaccines are related by some individuals, the yellow fever 17D virus is one of the most successful vaccines developed to date. Despite cell-mediated immunity has a pivotal role in generating an effective antibody response, the cellular and molecular mechanism by which 17D vaccine elicits such broad-based immunity is still unclear and few studies concerning the evaluation of the cellular immune compartment have been published. Recent studies developed by our group have demonstrated that simultaneous mechanisms of activation/modulation of the immune response are the basis of the antiviral protection triggered after the 17D-YF vaccination. This review summarizes important advances on YF immune response following natural infection and vaccination.