The introduction of Bacillus thuringiensis (Bt) cotton has reduced the burden of pests without harming the environment and human health. However, the efficacy of Bt cotton has decreased due to field-evolved resistance in insect pests over time. In this review, we have discussed various factors that facilitate the evolution of resistance in cotton pests. Currently, different strategies like pyramided cotton expressing two or more distinct Bt toxin genes, refuge strategy, releasing of sterile insects, and gene silencing by RNAi are being used to control insect pests. Pyramided cotton has shown resistance against different cotton pests. The multiple genes pyramiding and silencing (MGPS) approach has been proposed for the management of cotton pests. The genome information of cotton pests is necessary for the development of MGPS-based cotton. The expression cassettes against various essential genes involved in defense, detoxification, digestion, and development of cotton pests will successfully obtain favorable agronomic characters for crop protection and production. The MGPS involves the construction of transformable artificial chromosomes, that can express multiple distinct Bt toxins and RNAi to knockdown various essential target genes to control pests. The evolution of resistance in cotton pests will be delayed or blocked by the synergistic action of high dose of Bt toxins and RNAi as well as compliance of refuge requirement.