Plants produce a vast array of specialized metabolites that serve as essential defenses against herbivores and pathogens. However, the capacity to produce these compounds differs substantially among plant species and is frequently diminished during domestication. Advances in synthetic metabolic engineering enable efficient elucidation and engineering of plant specialized metabolic pathways active in crop pest and pathogen resistance. This review summarizes strategies and workflows for selecting defensive metabolic pathways, identifying candidate biosynthetic genes, and rewiring native or introducing heterologous pathways to enhance crop resistance to pests and pathogens. Strategies include weighted gene co-expression network construction, biosynthetic gene cluster scanning, and metabolite genome-wide association studies for pathway discovery, as well as transcriptional reprogramming, enzyme activity optimization, and transporter deployment for pathway engineering. We further discuss challenges in using synthetic metabolic engineering to enhance crop resistance and highlight the potential of artificial intelligence in addressing them.