Escherichia coli must actively transport many of its proteins to extracytoplasmic compartments such as the periplasm and outer membrane. To perform this duty, E. coli employs a collection of Sec (secretion) proteins that catalyze the translocation of various polypeptides through the inner membrane. After translocation across the inner membrane, periplasmic and outer-membrane proteins are folded and targeted to their appropriate destinations. Here we review our knowledge of protein translocation across the inner membrane. We also discuss the various signal transduction systems that monitor extracytoplasmic protein folding and targeting, and we consider how these signal transduction systems may ultimately control these processes.