Aphids are economically significant agricultural pests that are responsible for large yield losses in many different crops. Because the use of insecticides is restricted in the context of integrated pest management and aphids develop resistance against them rapidly, new biotechnology-based approaches are required for aphid control. These approaches focus on the development of genetically modified aphid-resistant plants that express protease inhibitors, dsRNA, antimicrobial peptides, or repellents, thus addressing different levels of aphid-plant interactions. However, a common goal is to disturb host plant acceptance by aphids and to disrupt their ability to take nutrition from plants. The defense agents negatively affect different fitness-associated parameters such as growth, reproduction, and survival, which therefore reduce the impact of infestations. The results from several different studies suggest that biotechnology-based approaches offer a promising strategy for aphid control.