Binding to a chemokine receptor, either CCR5 or CXCR4, by the gp120 glycoprotein is an essential step in the pathway by which HIV enters host cells. Recently, CCR5 antagonists have been developed that obstruct binding of CCR5 by gp120, thus inhibiting host cell entry. Resistance to such CCR5 antagonists may emerge, however, through the selection of viral strains capable of utilizing CXCR4 receptors. This study explores the evolutionary context of emergence, and in many cases decline, of dominant CXCR4-usage (X4) during disease progression within a number of individuals. Of seven individuals exhibiting a switch to dominant CXCR4 usage, such dominance is transient in five of them with CCR5-usage (R5) re-emerging to dominate the viral population later in disease progression. Three individuals conform to documented X4 transience in that the re-emergence of R5 dominance is an outgrowth from the predominant R5 strain. However, in two individuals we observe a novel pathway for R5 re-emergence in that R5 strains emerge to dominate late in disease progression through continued evolution of the X4 population. This suggests that the molecular mechanism of such switches between R5 and X4-usage is strain specific and that no single mechanism is shared between individuals. These findings have implications for the understanding of the mechanisms of potential emergence of resistance to CCR5 antagonists through use of the CXCR4 receptor and support the importance to have an appropriately optimized background therapy for use with entry inhibitors and, as for all HAART, to monitor drug resistance in a comprehensive manner. J. Med. Virol. 82:2004-2012,2010. (c) 2010 Wiley-Liss, Inc.