This paper aims to give an overview of the methods to inherently prevent human errors and to effectively mitigate the consequences of such errors by securing defense-in-depth during plant management through the advanced man-machine interface system (MMIS). It is needless to stress the significance of human error reduction during an accident in nuclear power plants (NPPs). Unexpected shutdowns caused by human errors not only threaten nuclear safety but also make public acceptance of nuclear power extremely lower. We have to recognize there must be the possibility of human errors occurring since humans are not essentially perfect particularly under stressful conditions. However, we have the opportunity to improve such a situation through advanced information and communication technologies on the basis of lessons learned from our experiences. As important lessons, authors explained key issues associated with automation, man-machine interface, operator support systems, and procedures. Upon this investigation, we outlined the concept and technical factors to develop advanced automation, operation and maintenance support systems, and computer-based procedures using wired/wireless technology. It should be noted that the ultimate responsibility of nuclear safety obviously belongs to humans not to machines. Therefore, safety culture including education and training, which is a kind of organizational factor, should be emphasized as well. In regard to safety culture for human error reduction, several issues that we are facing these days were described. We expect the ideas of the advanced MMIS proposed in this paper to lead in the future direction of related researches and finally supplement the safety of NPPs.