Finding new, effective antibiotics is a challenging research area driven by novel approaches required to tackle unconventional targets. In this review we focus on the bacterial protein secretion pathway as a target for eliminating or disarming pathogens. We discuss the latest developments in targeting the Sec-pathway for novel antibiotics focusing on two key components: SecA, the ATP-driven motor protein responsible for driving preproteins across the cytoplasmic membrane and the Type I signal peptidase that is responsible for the removal of the signal peptide allowing the release of the mature protein from the membrane. We take a bird's-eye view of other potential targets in the Sec-pathway as well as other Sec-dependent or Sec-independent protein secretion pathways as targets for the development of novel antibiotics. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.