The objective of this review is to describe the implementation of human factors principles for the design of alerts in clinical information systems. First, we conduct a review of alarm systems to identify human factors principles that are employed in the design and implementation of alerts. Second, we review the medical informatics literature to provide examples of the implementation of human factors principles in current clinical information systems using alerts to provide medication decision support. Last, we suggest actionable recommendations for delivering effective clinical decision support using alerts. A review of studies from the medical informatics literature suggests that many basic human factors principles are not followed, possibly contributing to the lack of acceptance of alerts in clinical information systems. We evaluate the limitations of current alerting philosophies and provide recommendations for improving acceptance of alerts by incorporating human factors principles in their design.