Voltage-gated sodium channels (VGSC) are critical determinants of cellular electrical activity through the control of initiation and propagation of action potential. To ensure this role, these proteins are not consistently delivered to the plasma membrane but undergo drastic quality controls throughout various adaptive processes such as biosynthesis, anterograde and retrograde trafficking, and membrane targeting. In pathological conditions, this quality control could lead to the retention of functional VGSC and is therefore the target of different pharmacological approaches. The present chapter gives an overview of the current understanding of the facets of VGSC life cycle in the context of both cardiac and neuronal cell types.