We review alternative hypotheses and associated mechanisms to explain Lake Victoria’s Nile perch (Lates niloticus) takeover and concurrent reduction in haplochromines through a (re)analysis of long-term climate, limnological, and stock observations in comparison with size-spectrum model predictions of co-existence, extinction, and demographic change. The empirical observations are in agreement with the outcomes of the model containing two interacting species with life histories matching Nile perch and a generalized haplochromine. The dynamic interactions may have depended on size-related differences in early juvenile mortality: mouth-brooding haplochromines escape predation mortality in early life stages, unlike Nile perch, which have miniscule planktonic eggs and larvae. In our model, predation on the latter by planktivorous haplochromine fry acts as a stabilizing factor for co-existence, but external mortality on the haplochromines would disrupt this balance in favor of Nile perch. To explain the observed switch, mortality on haplochromines would need to be much higher than the fishing mortality that can be realistically reconstructed from observations. Abrupt concomitant changes in algal and zooplankton composition, decreased water column transparency, and widespread hypoxia from increased eutrophication most likely caused haplochromine biomass decline. We hypothesize that the shift to Nile perch was a consequence of an externally caused, climate-triggered decrease in haplochromine biomass and associated recruitment failure rather than a direct cause of the introduction.