During the formation of the nervous system, axonal growth cones navigate through the complex environment of the developing embryo to innervate their targets. Growth cones achieve this formidable feat by responding to attractive or repulsive guidance cues expressed at specific points along the trajectory of their growth, which impart the directional information required for accurate pathfinding. While much is known about guidance molecules and their receptors, many questions remain unanswered. Which signal transduction pathways are activated within the growth cone after encountering a guidance cue? How is this related to rearrangement of the growth cone cytoskeleton? Do different cues use different signal transduction pathways? This chapter will review some of the work that has addressed these fundamental questions, with a specific focus on the role of the cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), in axon guidance.