Growth cones, the hand-like structures at the tip of growing neurites, possess remarkable abilities to detect directional cues. On their way to their targets they traverse a dense jungle of many different cells, expressing a variety of different molecular guidance cues. Proper reading and integration of these cues is essential for precise wiring of different parts of the peripheral and central nervous systems. Guidance cues have been classified according to the response they elicit as either attractive or repulsive. Recent work, however, suggests that this might not represent an absolute distinction and that the internal state of the growth cone can dictate whether it detects a cue as repulsive or attractive. This article reviews some new experimental approaches to understanding growth cone signal transduction mechanisms induced by extracellular guidance cues.