Cognitive impairment in schizophrenia (SCZ) is essential for this disease and is resistant to long-term treatment, refusing the patient's social life. Drug development for patients with SCZ remains challenging, given the absence of a unifying pathophysiology, and the highly complex underlying genetic architecture, and there are currently no approved drugs nor well-established treatments. Working memory is a fundamental brain process used to retain and recall information on the fly, and severely impaired in people with SCZ altering their reasoning, perception, and decision making. Recently, we discovered the histone demethylase LSD1 inhibitor, ORY-1001, that improves the impairment of working memory using a mouse model of SCZ caused by a loss-of-function rare mutation in the gene encoding for SETD1A, one of the histone methyltransferases that catalyze the methylation of lysine 4 residues in histone H3. This finding indicated that these SCZ-related epigenetic processes are ‘druggable”. Here, we present a new generation of epigenome therapeutic agents and methods for cognitive impairments in SCZ, targeting transcriptional networks regulated by chromatin remodeling complexes and transcription factors, focused on the recruitment of Setd1a to specific genomic target sets.