Extracellular matrix (ECM) proteins and their receptors, the integrins, actively participate in the control of many fundamental cellular functions in the developing nervous system, including the regulation of cell migration, differentiation, and survival and the control of neurite outgrowth. ECM-integrin interactions in the mature nervous system are commonly considered to be more static in nature and of little importance in the regulation of neuronal function. In contrast, we demonstrate that integrins and their ligands are capable of rapid neuromodulatory actions. Specifically, we show that integrin ligands can alter neuronal pacemaker properties, intracellular free Ca2+ levels, and voltage-gated Ca2+ currents in a matter of minutes. These findings indicate that ECM-integrin interactions play a dynamic role in regulating the physiological status of mature neurons, a process that may contribute to synaptic plasticity, neural regeneration, and neuropathology.