Type IV secretion systems are employed by a wide variety of Gram-negative microorganisms for the translocation of macromolecules across the cell envelope. The translocated substrates (proteins, protein-DNA complexes and DNA) are as diverse as the organisms on the donor and recipient side of the translocation process. Over the course of evolution, these macromolecular transporters were adapted to many different purposes, but their basic mechanism was conserved. They impact human life in various ways, as there are driving forces of horizontal gene transfer, which spreads biodegradative capabilities of environmental bacteria as well as antibiotic resistance of pathogens in hospitals. Also, they translocate toxins and other effectors, which have an effect on host cell metabolism and are essential for the virulence of bacterial pathogens. We here present recent developments of research on the mechanism of type IV secretion focusing on the energetization of transport and assembly processes, formation of the translocation channel and of surface-exposed pili, which initiate host cell interactions.