This paper introduces current issues, challenges, and future directions of nuclear thermalhydraulic (T-H) safety research, viewed in close conjunction with new developments in advanced reactor systems and simulation tools and lessons learned from the Fukushima accident. Two technical concerns are introduced to illustrate some of the limitations in our current understanding of important T-H phenomena that are very relevant to nuclear safety. The first is reflood heat transfer, which has been an important safety issue for a long time, and the second is the multidimensional T-H phenomena appearing in nuclear reactor systems, which have rather recently drawn significant attention in the nuclear community. These concerns are discussed by taking some recent research examples and emphasizing their critical relevance to nuclear reactor safety. Then, some challenging issues for the advancement of nuclear T-H safety technologies are identified and briefly discussed in close conjunction with recent research efforts, and perspectives on advanced nuclear T-H safety research are presented.