For a long time, hand, foot and mouth disease (HFMD) was seen as a mild viral infection characterized by typical clinical manifestations that spontaneously resolved in a few days without complications. In the past two decades, HFMD has received new attention because of evidence that this disease could have clinical, epidemiological and aetiological characteristics quite different from those initially thought. In contrast to previous beliefs, it has been clarified that HFMD can be associated with complications, leading to severe neurological sequelae and, rarely, to death. This finding has led to an enormous number of studies that have indicated that several viruses in addition to those known to be causes of HFMD could be associated with the development of disease. Moreover, it was found that if some viruses were more common in some geographic areas, frequent modification of the molecular epidemiology of the infecting strains could lead to outbreaks caused by infectious agents significantly different from those previously circulating. Vaccines able to confer protection against the most common aetiologic agents in a given country have been developed. However, simultaneous circulation of more than one causative virus and modification of the molecular epidemiology of infectious agents make preparations based on a single agent relatively inadequate. Vaccines with multiple components are a possible solution. However, several problems concerning their development must be solved before adequate prevention of severe cases of HFMD can be achieved.