Aerobic granular sludge has been regarded as a promising alternative to the conventional activated sludge which has been used for a century in that granular sludge offers advantages in high biomass retention, fast sludge-water separation, and small footprint requirement. However, this technology has been rarely applied in continuous flow reactors (CFRs) which are the most common type of bioreactors used in water resource recovery facilities across the world. Hence, the overarching goal of this study is to provide advanced understanding of biogranulation mechanism to enable industrial application of this technology. The lack of long-term stability study in CFRs has restricted its full-scale acceptability. The high settling velocity-based selection pressure has been regarded as the ultimate driving force towards biogranulation in sequential batch reactors (SBRs). In this study, this physical selection pressure was firstly weakened and then eliminated in CFRs to investigate its role in maintaining the long-term structural stability of aerobic granules. Given the fact that implementing settling velocity-based selection pressure only can cultivate biogranules in SBRs but not in completely stirred tank reactors (CSTRs), the essential role of feast/famine conditions was investigated. Seventeen sets of data collected from both literature and this study were analyzed to develop a general understanding of the granulation mechanisms. The outcome indicated that granulation is more sensitive to the feast/famine conditions than to the settling velocity-based selection pressure. The theory was tested in a CFR with 10-CSTR chambers connected in series to provide feast/famine conditions followed by a physical selector separating the slow-settling bioflocs and fast-settling biogranules into feast and famine zones, respectively. Along with successful biogranulation, the startup performance interruption problem inherent in SBRs was also resolved in this innovative design because the sludge loss due to physical washout selection was mitigated by returning bioflocs to the famine zone. Then, a cost-effective engineering strategy was put forward to promote the full-scale application of this advanced technology. With this generalized biogranulation theory, pure culture biogranules with desired functions for high value-added bioproducts were also investigated and achieved for the first time in this study, which paves a new avenue to harnessing granulation technology for intensifying waste valorization bioprocesses.