Sepsis and multiple sclerosis are immunological disorders defined by an over-response of the immune system to the body’s own tissues. Several G protein-coupled receptors (GPCRs), including the adenosine A2A receptor (A2AAR) and the first sphingosine-1 phosphate receptor (S1PR1), play a role in the immune system. Activation of the A2AAR on lymphocytes is anti-inflammatory, because the activation of the receptor inhibits pro-inflammatory cytokines, such as TNF-, while the S1PR1 is pro-inflammatory by promoting lymphocyte circulation. In this dissertation, I applied a computational approach to explore the activation pathways of the A2AAR and the S1PR1, and a structural-based drug design approach to identify potential modulators for the treatment of immunological disorders. The deactivation process of the A2AAR was characterized from long time-scale molecular dynamics simulations. Four conformers of the A2AAR during deactivation were identified, including the active, intermediate 1, intermediate 2, and inactive. The non-orthosteric binding sites in each conformer of the receptor were identified. Activation of the S1PR1, initiated by a rotameric switch of residue W2686.48, was captured with accelerated molecular dynamics simulations. Eight non-orthosteric binding sites were identified on the S1PR1, and 39 potential orthosteric and allosteric modulators were discovered. These modulators are being tested for activity on the S1PR1.