Neurodegenerative disease appears as a result of genomic lesions which lead to alterations at multiple levels like genomic product and biological pathways. It involves destruction of existing neuroprotective mechanisms inside body which initiates the cellular changes involved in processing of these insidious disorders. Phosphodiesterases that are crucial for degradation of cAMP and cGMP have been puissant in memory retrieval. Overwhelming therapeutic credential of PDE5 inhibitors have triggered interests in PDE inhibitors. Almost every PDE member has marked its presence in the CNS devising them as enticing sources of novel protein targets for curing ND. This review describes a selection of recent findings and advancements with regards to PDE genes that are crucial for exploring pharmacological routes to ND.