The homeostatic regulation of membrane excitability provides stability to the neural network in the face of dynamic and plastic synaptic inputs. This is mediated by a number of ion channels expressed in different membrane domains of neurons. The Kv2.1 voltage-gated potassium channel is a delayed rectifier channel with a small single channel conductance (~10 pS), slow deactivation, and a relatively high-threshold for voltage-dependent activation (G1/2≈ +15 mV). This channel is highly concentrated in the proximal domain of neurons, the soma and proximal dendrites, where it can effectively regulate the overall excitability of neurons. We have shown that increased neuronal activity results in dephosphorylation of Kv2.1 through a Ca2+-dependent signaling pathway and phosphatases. Dephosphorylation of the cytoplasmic C-terminus shifts the voltage-dependent activation of Kv2.1 to lower membrane potentials. Together with the slow deactivation of Kv2.1, the change in activation dramatically increases the availability of the K+ channel during a train of action potential firing. This in turn provides the activity-dependent suppression of neuronal excitability, which can be reversed by blocking Kv2 channels. The efficient suppression of neuronal excitability by Kv2.1 is in part due to its localization in the proximal domain of neurons, where synaptic potentials are integrated to determine the rate of action potential firing. Protein trafficking of Kv2.1 in the proximal domain of neurons is mediated by unique molecular mechanisms. We recently found that Kv2.1 is transported in a specific population of transport vesicles, of which motion is driven by a myosin and actin filaments. Because of the organization of actin filaments, determined by a super-resolution microscopy, and the property of the motor, the transport of vesicles carrying Kv2.1 is restricted in the proximal domain. Furthermore, we recently found that the trafficking mechanism is regulated by neuronal activity through NMDA receptors. I will discuss the potential role of this phenomenon in the homeostatic regulation of neuronal excitability by Kv2.1 channel.