We investigated the roles of Toll‐like receptor 2 (TLR2) and myeloid differentiation factor 88 (MyD88) in the course of a lymphocytic choriomeningitis virus (LCMV) infection and revealed the following: (i) studies of transfected cells and murine peritoneal macrophages demonstrated that TLR2 and MyD88 are essential for the initial pro‐inflammatory cytokine response (human IL‐8, mouse IL‐6) to LCMV; (ii) TLR2 knockout (KO) mice and MyD88 KO mice challenged with LCMV produced less IL‐6 and monocyte chemotactic protein‐1 in the serum than wild‐type mice; (iii) in contrast to inflammatory cytokines, the production of type 1 IFN (IFN‐α) in response to LCMV was MyD88 independent; (iv) MyD88 plays an essential role in antiviral CD8⁺ T cell responses, CD8⁺ T cells in MyD88 KO mice were defective in their expression of intracellular antiviral cytokines; and (v) the failure of MyD88 KO mice to activate CD8⁺ T cells was accompanied by persistent viral infection in MyD88 KO mice. We demonstrate that TLR‐mediated responses are important in the innate immune response to LCMV and that MyD88 is essential for the control of the LCMV infection and the maturation/activation of virus‐specific CD8⁺ T cells.