Organisms with bilateral symmetry elaborate patterns of neuronal projections connecting both sides of the central nervous system at all levels of the neuraxis. During development, these so-called commissural projections navigate across the midline to innervate their contralateral targets. Commissural axon pathfinding has been extensively studied over the past years and turns out to be a highly complex process, implicating modulation of axon responsiveness to the various guidance cues that instruct axon trajectories towards, within and away from the midline. Understanding the molecular mechanisms allowing these switches of response to take place at the appropriate time and place is a major challenge for current research. Recent work characterized several instructive processes controlling the spatial and temporal fine-tuning of the guidance molecular machinery. These findings illustrate the molecular strategies by which commissural axons modulate their sensitivity to guidance cues during midline crossing and show that regulation at both transcriptional and post-transcriptional levels are crucial for commissural axon guidance.