Guayule (Parthenium argentatum) is a woody shrub native to the southwestern US that produces rubber in its stems. In the production of guayule hard rubber for tires, two residue streams are produced: a complex resin liquid and a ground, dry woody bagasse. Identifying higher-value products and applications for these residues is a goal of the Logistics and Co-Products thrust of the Sustainable Bioeconomy for Arid Regions (SBAR) USDA Coordinated Agricultural Project. Here, we summarize the current knowledge of guayule resin chemical composition, extraction methods used to isolate guayule resin fractions, and promising applications for these fractions. The most abundant compounds include terpenes and terpenoids, phenolics, alkaloids, sterols, and fatty acids/triglycerides, and low-molecular-weight rubber. Unique to guayule are guayulins and argentatins, which are expected to have some degree of bioactivity. Common extraction methods include Soxhlet extraction, steam distillation, maceration, percolation, pressurized- liquid extraction, supercritical fluid extraction, ultrasound-assisted extraction, microwave-assisted extraction, and several other experimental techniques. Resin mixtures are extremely complex, ranging from volatile to non-volatile, and from thermally stable to very delicate, molecules. Potential applications include tackifiers, adhesives, coatings, composite components, and those for essential oils: bio-control agents, insecticides, antimicrobials, antifungals. Separation optimization focuses on maximizing total economic value of extractable fractions, increasing the scale and robustness of extraction methods, and lowering the operational costs and environmental impacts of extraction processes.