The increasing trend of antibiotic resistance in bacterial pathogens has driven the need for new classes of antibiotics acting by novel mechanisms. The arylomycins are natural product antibiotics that inhibit bacterial type I signal peptidase (SPase), an endoprotease that is required for the translocation of most proteins across the cytoplasmic membrane. SPase is a promising antibiotic target due to its essentiality and its conserved and accessible active site. However, the initial reported spectrum of arylomycin activity was surprisingly narrow. The total synthesis of several members of this fascinating family of natural products has allowed for a more thorough study of its activity. It has been shown that their spectrum of activity is much broader than previously believed, and that their activity is generally limited not by factors intrinsic to their scaffold or to SPase as a target, but rather, by specific mutations in SPase. An interesting possibility is that past competition between producer and susceptible strains of bacteria may have led to the development of much of the intrinsic resistance observed today. The arylomycins may thus represent “latent” antibiotics, natural product antibiotics whose scaffolds once possessed potent and broad-spectrum activity, and are more likely to be optimized to again have potent and broad spectrum activity, than candidate scaffolds that have never been antibiotics.