The degradation of voltage-gated calcium channels (VGCC), which are key determinants of neuronal excitability and muscle contraction, is crucial for regulating calcium homeostasis and can be targeted for analgesic drug discovery. Molecularly, both the ubiquitin-proteasomal system and lysosomal pathways play critical roles in VGCC turnover with the involvement of ubiquitin-conjugating E2 enzyme UBE2L3, multiple ubiquitin-ligating E3 ligases including Rfp2, Mdm2, Nedd4-1 and WWP1, and deubiquitinase USP5. Physiologically, a blocking peptide and small molecules interfering with the Ca3.2-USP5 protein interaction has been developed to treat neuroinflammation and neuropathic pain in mouse models. Moreover, two genetically encoded calcium channel blockers by using catalytic HECT domain of the E3 ubiquitin ligase Nedd4-2 and nanobodies to β subunit and Nedd4-2 have been shown to have exceptional potency to remove high voltage-gated calcium channels from the plasma membrane. These two blockers showed strong efficacy in reducing hyperalgesia response to nerve injury. Therefore, a deeper understanding of VGCC degradation offers new therapeutic strategies for diseases associated with calcium channel dysfunction, including neuroinflammation, Parkinson's disease, neuropathic pain and cardiovascular diseases.