The eastern Himalayan syntaxis is one of the regions having the most intense tectonic activities, the most complex geological conditions, and the most frequent geohazards in the world. The planning and construction of engineering projects are faced with four types of catastrophic geo-safety risks, including tectonic faulting in the plate tectonic belt, disaster occurrence of the deep-buried tunnels, instability of loose mountains, and regional geological disaster chain. It is a critical topic in the field of engineering geology how to select relatively stable and safe sites in active tectonic zones to minimize the geo-safety risks of planning, construction, and operation of engineering projects. This paper summarized the major geo-safety problems in the eastern Himalayan syntaxis. Accordingly, it revealed that traditional site selection theories hardly satisfy the requirements of the engineering projects in the eastern Himalayan syntaxis area. The site selection encounters geo-safety challenges caused by unclear geological evolution process and construction, prominent disaster risk of tectonic activity and strong earthquake, weak research on the deep tectonic stress field and disaster evaluation, and severe ultra-high-elevation and ultra-long-runout geological disaster chain. Thus, this paper suggested the main research directions of the site selection from five aspects: (1) regional geological evolution and engineering geological problems, (2) active fault and engineering safety risk, (3) complex in-situ stress field and engineering disaster risk, (4) engineering risk of regional geological disaster chain, and (5) theory and method of site selection in eastern Himalayan syntaxis. This paper provides ideas for improving the risk assessment and prevention methods of site selection of engineering projects. [ABSTRACT FROM AUTHOR]