Clinical decision support systems (CDSS) are designed to help making clinical decisions regarding the management of patients. CDS alerts can save lives but frequent insignificant ones might cause alert fatigue. Studies discuss that 33% to 96% of clinical alerts are ignored. We categorized best evidence based strategies, to reduce alert fatigue and improve CDSS utilization, into five major areas. Classify alerts in to three main levels; severe, moderate and minor then develop a core set of critical drug to drug interactions. Classify alerts into active and passive groups, where only critical alerts should be interruptive actively while less critical alerts should be non-interruptive to the user. Conduct regular user training on new improvements. Keep monitoring alert response rates and keep ongoing research and improvement efforts. Provide systems with automated feedback and learning mechanisms where frequently ignored and justified alerts could be moved automatically from the active interruptive to the passive non-interruptive model.