Epigenetic chromatin remodeling and signalling pathways play an integral role in transcription dependent neurodegeneration and long-term potentiation (LTP), a cellular model associated with learning and memory. Pathological epigenetic modifications associated with neurological disorders are inherently flexible and can be reversed through pharmacological intervention. Small molecules are the favored drugs for clinicians, and in neurological disorders associated with complex cellular mechanisms, epigenetic and/or signalling pathway enzymes inhibiting small molecules have shown clinical prospects. Recently, small molecules with two or more functionalities, such as sequence-specific recognition and signalling pathways and/or enzyme modulation, have shown capabilities as efficient transcriptional activators. Here, we give a balanced overview of the key factors associated with memory recovery and neurodegeneration, available chemical tools for modulation and the demand to develop next-generation small molecules with multi-functional activities to treat such intricate, multi-gene associated neurological disorders.