Foot-and-mouth disease virus (FMDV), which causes a highly contagious viral disease of cloven-hoofed animals, is notable for epithelial cell tropism, resulting in the appearance of vesicles on the feet and in and around the mouth in infected animals, while FMDV infection in neonatal animals is also associated with not only epithelial lesions, but also muscle-associated lesions, which leads to myocarditis, resulting in high-mortality. However, critical knowledge about the non-epithelial tropism of FMDV is still lacking. In this paper, the current progress of the FMDV non-epithelial tropisms is summarized and the possible role of the key viral and cellular components involved is discussed.