To engineer plants with increased and durable disease resistance using transgenic technologies we must address two questions. First, what gene or genes do we want to express to improve disease resistance, and second, how are we going to express these genes so that crop yields are actually increased? Emerging technologies are providing us with a plethora of candidate genes that might lead to enhanced crop protection through genetic engineering. These genes can come from plants, from pathogens or from other organisms and several strategies for their manipulation show promise. Here, we discuss recent advances and consider future perspectives for producing plants with durable disease resistance.