Dengue virus (DENV) pathogenesis seems to be determined by numerous, interacting factors: viral virulence, host immunity and immune status, host genetics and possibly others (e.g., preexisting diseases). Because we have no models of severe dengue disease (DHF), all associations of viruses with increased pathogenesis have been indirect and painstakingly slow in being developed. Transmissibility has also been measured indirectly: the successful isolation of viruses from patients and the preponderance of one serotype over another have been documented in numerous countries but this has also introduced biases in our sampling. We do not have available a fully representative set of DENV genomes to study and understand what truly constitutes the natural range of DENV variation; many samples from mosquitoes or less-ill human infections are missing, in addition to those from countries lacking the laboratory and public health infrastructure necessary for detecting and isolating viruses. Virus-mosquito interactions also add a layer of complexity to the determination of which genotype is being transmitted and we are only beginning to measure the effects of this selection. However, many new methods have been applied to the study of DENV genetic variation, replication fitness and their effects on transmissibility and pathogenesis in humans. None of these methods are perfect and we must still regard them as surrogates for measurements of the natural viral determinants of disease. Thus, understanding this complex system will probably require multidisciplinary approaches to solving the mysteries of the interaction of the many factors that contribute to DENV epidemiology. Other, nonviral factors contributing to DENV pathogenicity and transmission are discussed in accompanying chapters.