Integrin receptors are required for cell adhesion, migration, survival, and proliferation of cells when in contact with the extracellular matrix. In addition, integrins are required for the outgrowth of neurites and formation of glial scaffold in the brain and also for the remodeling and long-term potentiation within synapses. While some of these neuronal functions are expected from studies in nonneuronal cells, such as fibroblasts, other functions, especially at synapses, cannot be studied elsewhere. In this chapter, we will concentrate on the mechanisms that control integrin-mediated signaling and how it is initiated downstream of integrin-ligand interaction. While we address some newer findings concerning the recruitment of paxillin to the integrin-talin-kindlin complex, we will also highlight the central function of paxillin in integrin signaling and how it can interface with other signaling systems controlling neuronal or synaptic functions.