Since 1996, transgenic Bacillus thuringiensis (Bt) cotton has been commercially grown in numerous countries in an effort to stem the losses caused by key lepidopteran pests. However, the development of pest resistance to Bt toxins has jeopardized the continued utilization of Bt cotton. As a strategy designed to circumvent the development of resistance, Bt cotton varieties expressing two or more toxins targeting the same pest have been introduced. Nevertheless, from the perspective of long-term planting of Bt cotton, the potential risk of cross-resistance to these Bt toxins is a threat that cannot be ignored. In this paper, we review current research (including that based on the analysis of protein binding sites and resistance genes) on the resistance of cotton bollworm (Helicoverpa armigera) to the Bt toxins Cry1Ac and Cry2Ab and the interrelationship between these toxins. On the basis of existing evidence, we assume that the actions of Cry1Ac and Cry2Ab against cotton bollworm are not completely independent, and then propose the resistance-associated gene mutation potential hypothesis. Although the mechanisms underlying the resistance of pests to Bt toxins are yet to be comprehensively elucidated, this hypothesis could undoubtedly have important implications for adopting pyramid strategy in the future. Further research is recommended to devise strategies to retard the development of H. armigera resistance to Bt cotton, either using different Bt toxins or their various combinations.