Aphids are demonstrated to be voracious phloem feeders, among the most damaging insect pests, due to their capacity to decrease crop production and vector plant viruses. Plant secondary metabolites (PSMs) comprise an essential element of plant protection, which in most cases deters and affects aphid performance. Nonetheless, aphids have developed various resistance mechanisms to counteract these chemicals. This review provides an extensive overview of the biological and molecular adaptations that aphids employ to counteract PSMs, including enzymatic detoxification, antioxidant defense, sequestration, behavioral response shifts, suppression of plant defense mechanisms by symbionts, and manipulation of host signaling pathways by effector proteins. We also described the suppression of the defense pathways by aphid-associated viruses, which further complicates plant–aphid interactions. Although significant insights have been gained about each of the individual mechanisms, research gaps remain, particularly in the functional confirmation of detox genes, the communication interactions of the symbionts, and whether sequestration could play an ecological role across species. Intensive efforts involving molecular-based breeding of horticultural crops, as well as traditional breeding with wild relatives highly endowed with aphid-resistant PSM traits, should be employed in the future to provide sustainable crop protection. New technologies in crop genomics, the identification of effectors, and microbiome research promise the development of resistant cultivars that are not only resistant to aphids but also prevent the spread of disease by their vectors. Together, all this knowledge has the potential to produce high-yielding crops that are resistant to aphids and to implement sustainable farming practices.