The transition between the B and Z conformations of double-helical deoxyribonucleic acid (DNA) belongs to the most complex and elusive conformational changes occurring in biomolecules. Since the accidental discovery of the left-handed Z-DNA form in the late 1970s, research on this DNA morphology has been engaged in resolving questions relative to its stability, occurrence, and function in biological processes. While the occurrence of Z-DNA in vivo is now widely recognized and the major factors influencing its thermodynamical stability are largely understood, the intricate conformational changes that take place during the B-to-Z transition are still unknown at the atomic level. In this article, we report simulations of this transition for the 3'-(CGCGCG)-5' hexamer duplex using targeted molecular dynamics with the GROMOS96 force field in explicit water under different ionic-strength conditions. The results suggest that for this oligomer length and sequence, the transition mechanism involves: 1), a stretched intermediate conformation, which provides a simple solution to the important sterical constraints involved in this transition; 2), the transient disruption of Watson-Crick hydrogen-bond pairing, partly compensated energetically by an increase in the number of solute-solvent hydrogen bonds; and 3), an asynchronous flipping of the bases compatible with a zipperlike progression mechanism.