This article highlights the fundamental discoveries in plant defense, plant and pathogen genomes, and in microbial and pest infection strategies that can be harnessed by plant biotechnologists. This wealth of new knowledge has already led to the first generation of plant genetic engineering solutions created to provide durable and broader spectrum pathogen and pest resistance in many crop species. Particular emphasis is placed on the novel targeted approaches devised to control plant disease and plant damage caused by fungi, oomycetes, bacteria, nematodes, and insects. The possible ways by which plant biotechnology options can be further enhanced to maximize the likelihood of delivering longer lasting crop protection locally and globally are also discussed.