Invading pathogens are recognized by mammalian cells through dedicated receptors found either at the cell surface or in the cytoplasm. These receptors, like the trans-membrane Toll-like Receptors (TLR) or the cytosolic Nod-like Receptors (NLR), initiate innate immunity after recognition of molecular patterns found in bacteria or viruses, such as LPS, flagellin, or double-stranded RNA. Recognition of molecules produced only by a specific pathogen, such as a viral envelop protein or a bacterial adhesin does not appear to occur. Bacterial protein toxins, however, might compose an intermediate class. Considering the diversity of toxins in terms of structure, it is unlikely that cells respond to them via specific molecular recognition. It rather appears that different classes of toxins trigger cellular changes that are sensed by the cells as danger signals, such as changes in cellular ion composition after membrane perforation by pore-forming toxins or type III secretion systems. The signaling pathways triggered through toxin-induced cell alterations will likely play a role in modulating host responses to virulent bacteria. We will here describe the few studied cases in which detection of the toxin by the host cell was addressed. The review will include not only toxins but also bacteria effectors secreted by the bacterium in to the host cell cytoplasm.