The intestinal pathogen Clostridium difficile is known to grow only within the intestines of mammals, yet little is known about how the bacterium subsists in this environment. In the intestine, C. difficile must contend with innate defenses within the host, such as cationic antimicrobial peptides (CAMPs) produced by the host and the indigenous microbiota. In this study, we investigated the mechanism of activation and regulation of the CprABC transporter system, which provides resistance to multiple CAMPs and shows homology to the immunity systems of bacterial antimicrobial peptide producers. The CprABC system proved to be controlled by a noncontiguous two-component system consisting of the CprK sensor kinase and an orphan response regulator (CD3320; CprR). The CprK-CprR regulators were shown to activate cprABCK transcription in a manner similar to that by lantibiotic regulatory systems. Unlike lantibiotic producer regulation, regulation by CprK-CprR was activated by multiple lantibiotics produced by diverse Gram-positive bacteria. We identified a motif within these lantibiotics that is likely required for activation of cpr. Based on the similarities between the Cpr system and lantibiotic systems, we propose that the CprABC transporter and its regulators are relatives of lantibiotic systems that evolved to recognize multiple substrates to defend against toxins made by the intestinal microbiota.