The first targets of DENV replication, after mosquito bite, were postulated to be monocytes or macrophages and numerous studies focused on these cell types. However, more recent studies, using newer technologies for cell identification (mainly flow cytometry) have shown that DENV infects human monocytes poorly compared to dendritic cells, including Langerhans cells and monocyte-derived dendritic cells (Marovich et al. 2001; Wu et al. 2000) . Primary dendritic cell cultures can be derived from human peripheral blood donations to banks and this is the usual source for studies to compare the replication of low-passage DENV from patients. Because these samples are obtained anonymously, we must be careful to obtain them from blood banks in areas where there is no DENV transmission (i.e., no antigenic priming of cells) and we cannot determine the human genetic background that might lead to differences in virus replication. However, studies reported in 2003 (Cologna et al. 2005 Cologna and Rico-Hesse 2003) were able to show consistent differences in replication of DENV of two genotypes of serotype 2, demonstrating that there is an ex vivo correlation to the virulent phenotype derived from evolutionary studies. Although there seem to be innate, probably genetic differences in the yields of virus produced by cells from individual donors, this variation could be accounted for statistically and the correlations with virulence of patient-derived viruses were established (and note that these differences occur in the absence of antibodies). These primary cell cultures were also used to test recombinant viruses, to determine the influence of specific genome regions on virus replication and yields from human cell targets. These studies confirmed that the exchange of three genomic regions (5 0 and 3 0 UTRs, and E390) could reduce the levels of replication and virus yields of a Southeast Asian virus to those of wild-type, less virulent viruses of the American genotype (Cologna and Rico-Hesse 2003) . Other uses for cultured primary human cells include the identification of specific cells that are producing more virus (tropism) and whether virus replication is even required for pathologic effects.