Significant challenges remain in tackling the global HIV/AIDS epidemic. Effective action requires both appropriate policy at a global level and informed practice on the local level. Here, we report how workers in a project in Johannesburg, South Africa, make sense of HIV transmission. Discourse analysis of data from interviews with 63 participants shows that project workers routinely attribute transmission to men’s sexual relationships with multiple female partners. This explanation is so pervasive that it renders invisible other routes to transmission. Absence of consideration of other routes to infection potentially restricts front-line practice, so hindering local attempts to tackle HIV/AIDS.