Over the past decade, many publications have described experiments in which the recombinant monomeric form of the gp120 surface envelope (Env) glycoprotein of human immunodeficiency virus type 1 (HIV-1) has been added to cells in vitro (Fig. 1). The ensuing cellular responses (eg, activation of signal transduction pathways resulting in cytokine release, chemotaxis, proliferation, anergy, or apoptosis) are monitored. The outcome is generally that gp120 can kill a target cell or perturb its normal functions, and it is assumed that what is observed in vitro is relevant in vivo. Our intent is to question whether such an extrapolation is reasonable on quantitative grounds, particularly when the presence of antibodies (Abs) in the plasma of HIV-1-infected persons is taken into account. We cite only a small selection from this abundant literature, to illustrate the range of active gp120 concentrations reported. In the in vitro experiments, the gp120 concentrations vary from 1 pM to 1 AM (ca. 0.12 ng/ml to 120 Ag/ml, as 1 nM c 0.12 Ag/ml, eg Arthos et al., 2002; Chirmule et al., 1990; Davis et al., 1997; Esser et al., 2001; Goldman et al., 1994; Herbein et al., 1998; Hesselgesser et al., 1998; Huang et al., 2001; Kanmogne et al., 2001; Keswani et al., 2003; Kornfeld et al., 1988; Mann et al., 1987; Masci et al., 2003; Munshi et al., 2003; Oyaizu et al., 1990; Schneider-Schaulies et al., 1992; Tamma et al., 1997; Vlahakis et al., 2003; Wahl et al., 1989; Weinhold et al., 1989; Weissman et al., 1997; Yao et al., 2001). Sometimes biological effects occur only at the higher end of the range, although particularly in neuronal cell systems lower gp120 concentrations can be active. In those systems, the primary effects may be partly on microglial cells, which are reported to amplify secondary effects on neurons (cf. Garden, 2002; Kaul and Lipton, 1999; Keswani et al., 2003, reviewed in Kaul et al., 2001).