Advances in the genetic modification of organisms are creating new opportunities for the control of insect pests of both agriculture and public health significance. The timing and sex specificity of lethal transgene activation can be tailored to enhance the pest population control efficiency of mass-released, genetically modified insects. We developed mathematical models to determine the optimal timing and sex specificity of lethal transgene activation for the control of different types of pest population. We show that optimal release strategies are not only sensitive to the parameters governing growth of the population but also can be drastically affected by the inclusion of insect stage structuring, competition, and space. We emphasize the necessity of including these additional levels of complexity in future theoretical assessments as they are likely important considerations for designing transgenic organisms as well as their application in genetic control.