Vaccines and extended vaccination programs have had an extensive impact on morbidity and mortality rates due to infectious diseases. Because of the continuous and extensive use of vaccines in industrialized countries, many infectious diseases such as poliomyelitis, diphtheria and measles have been reduced to near-extinction. However, in recent years, many countries including the United States of America, the United Kingdom and Belgium, have been confronted with a resurgence of mumps and pertussis, despite high vaccination coverage for both vaccines. In this commentary, possible causes of this resurgence will be discussed, such as the occurrence of adapted microbes, failure to vaccinate and primary and secondary vaccine failure. Additional research of the immunological mechanisms is clearly needed to support the development of possible new and more immunogenic vaccines against mumps and pertussis. Meanwhile, extensive vaccination campaigns with both vaccines remain necessary.