The mammalian cerebral cortex requires the proper formation of exquisitely precise circuits to function correctly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. Although the development of the cerebral cortex has been well described anatomically, the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections are just beginning to be understood. Moreover, despite evidence that coordinated patterns of activity underlie reorganization of brain circuits during critical periods of development, the molecular signals that translate activity into structural and functional changes in connections remain unknown. Recently, the neurotrophins have emerged as attractive candidates not only for regulating neuronal differentiation in the developing brain, but also for mediating activity-dependent synaptic plasticity. The neurotrophins meet many of the criteria required for molecular signals involved in neuronal differentiation and plasticity. They are present in the cerebral cortex during development and their expression is regulated by synaptic activity. In turn, the neurotrophins themselves strongly influence both short-term synaptic plasticity and long-term potentiation and depression. In addition to their functional effects, the neurotrophins also profoundly regulate the structural changes that underlie axonal and dendritic differentiation. Finally, the neurotrophins have been implicated in mediating synaptic competition required for activity-dependent plasticity during the critical period. This chapter presents and discusses the rapidly accumulating evidence that the neurotrophins are critical for neuronal differentiation and that they may be involved in activity-dependent synaptic refinement in the developing cerebral cortex.