Apple and citrus are perennial tree fruit crops that are vital for nutritional security and agricultural economy and to achieve the Sustainable Development Goals of the United Nations. Apple scab and fire blight, along with Huanglongbing, canker, and tristeza virus, stand out as their most notorious diseases and annually destabilize fruit supply. An environmentally sound approach to managing these diseases is improving tree resistance through breeding and biotechnology. Perennial fruit tree germplasm collections are distributed globally and offer untapped potential as sources of resistance. However, long juvenility, specific pollination and flowering habits, and extensive outcrossing hinder apple and citrus breeding. Advances in breeding approaches including trans- and cis-genesis, genome editing, and rapid-cycle breeding, which, in addition to conventional crossbreeding, can all facilitate accelerated integration of resistance into elite germplasm. In addition, the global pool of available sources of resistance can be characterized by the existing genetic mapping and gene expression studies for accurate discovery of associated loci, genes, and markers to efficiently include these sources in breeding efforts. We discuss and propose a multitude of approaches to overcome the challenges of breeding for resistance in woody perennials and outline a technical path to reduce the time required for the ultimate deployment of disease-resistant cultivars.