Foot-and-mouth disease virus (FMDV) causes an economically devastating disease of cloven-hoofed animals. In this review, we discuss the mechanisms FMDV has evolved to counteract the host innate and adaptive immune responses and the role of viral proteins in this process. The viral leader proteinase, L pro, limits the host innate response by inhibiting the induction of interferon beta (IFN beta) mRNA and blocking host cell translation. A second viral proteinase, 3C pro, may affect host cell transcription because it cleaves histone H3. Viral protein 2B in conjunction with 2C or their precursor 2BC inhibits protein trafficking through the endoplasmic reticulum and Golgi apparatus. A decrease in surface expression of major histocompatibility class I molecules during FMDV infection suggests that 2B, 2C and/or 2BC may be involved in delaying the initiation of the host adaptive immune response and also adversely affect the secretion of induced signaling molecules. FMDV also causes a transient lymphopenia in swine, but the mechanism involved is not understood nor have any viral protein(s) been implicated. Furthermore, the interaction of FMDV with various cells in the immune system including lymphocytes and dendritic cells and the possible role of apoptosis and autophagy in these interactions are discussed.