Membrane vesicles, such as OMVs, released by Gram-negative bacteria contribute to infectious diseases. Understanding how these vesicles affect immune responses promises the development of new approaches to prevent infections. We have discovered that bacterial membrane vesicles activate several receptors in front line immune cells, such as macrophages. This includes cytosolic cell death receptors that trigger an inflammatory form of cell death, termed pyroptosis. In contrast, bacterial membrane vesicles from human pathogens fail to effectively activate pyroptosis, but instead trigger apoptosis. We will discuss the role of host factors in sensing bacterial membrane vesicles and how this affects macrophage responses and inflammation.