Bacteria use small secreted chemicals or peptides as auto-inducers to coordinately regulate gene expression within a population in a process called quorum sensing. Quorum sensing controls several important functions in different bacterial species, including the production of virulence factors and biofilm formation in Pseudomonas aeruginosa and bioluminescence in Vibrio fischeri. Many gram-negative bacterial species use acyl homoserine lactones as auto-inducers that function as ligands for transcriptional regulatory proteins. Several recent reports indicate that bacterial acyl homoserine lactones can also affect gene expression in host cells. Direct signaling also appears to function in the opposite direction as some eukaryotic cell types produce mimics that interact with quorum sensing systems in bacteria. Here, we will describe the evidence to support the existence of bi-directional inter-kingdom signaling via acyl homoserine lactones and eukaryotic mimics and discuss the potential molecular mechanisms that mediate these responses. The functional consequences of inter-kingdom signaling will be discussed in relation to both pathogenic and non-pathogenic bacterial-host interactions.