HIV-1 infection of macrophages, through the expression of the HIV-1–derived protein Nef, pushes macrophages to adopt the “mesenchymal” mode of migration through effects upon the src-family kinase Hck and a downstream effector, Wiskott-Aldrich syndrome protein (WASP). Migratory macrophages that employ the mesenchymal mode are better able to invade dense extracellular matrix and tissues. Results from Vérollet et al provide a mechanistic understanding of the increased infiltration of macrophages observed in HIV-infected patients. Professional illustration by Patrick Lane, ScEYEnce Studios.