By the last decade of the 20th century Aedes aegypti and the 4 dengue viruses had spread to nearly all countries of the tropical world. Some 2 billion persons live in dengue-endemic areas with tens of millions infected annually. The 20th century dengue pandemic has brought with it the simultaneous circulation of multiple serotypes and, in its aftermath, endemic dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Nearly 3 million children have been hospitalized with this syndrome in the past 3 decades, mainly in South-East Asia. Recent outbreaks of DHF/DSS in the Pacific Islands, China, India, Sri Lanka, Cuba, and Venezuela are indicators of the high intensity and rapid spread of dengue transmission. A key question why DHF/DSS does not occur with all second dengue infections has been attributed to: 1) a human resistance gene. Data from the 1981 DHF/DSS epidemic in Cuba have demonstrated the existence in Blacks of a resistance gene. 2) The existence of dengue biotypes. Some, but not all, biotypes may cause DHF/DSS during a second dengue infection. A South-East Asian dengue 2 biotype introduced into Cuba is thought to be responsible for the 1981 DHF/DSS epidemic. A recent study in Thailand suggests that when antibody residual from the first infection is able to neutralize a second virus type, a secondary infection will occur, but its severity is down-regulated and the disease mild. When no cross-reactive neutralizing antibodies are raised, a second infection is under the influence of enhancing antibodies; the resulting infection and disease are severe. The presence or absence of antigens on both the first and second virus determine disease severity. Enhanced surveillance for DHF/DSS and improved research including the study of pre- and post-epidemic sera and the isolation of viruses from serologically documented cases is lacking in most countries.