Cullins are crucial components of the ubiquitin–proteasome system, playing pivotal roles in the regulation of protein metabolism. This review provides insight into the wide-ranging functions of cullins, particularly focusing on their impact on plant growth, development, and environmental stress responses. By modulating cullin-mediated protein mechanisms, researchers can fine-tune hormone-signaling networks to improve various agronomic traits, including plant architecture, flowering time, fruit development, and nutrient uptake. Furthermore, the targeted manipulation of cullins that are involved in hormone-signaling pathways, e.g., cytokinin, auxin, gibberellin, abscisic acids, and ethylene, can boost crop growth and development while increasing yield and enhancing stress tolerance. Furthermore, cullins also play important roles in plant defense mechanisms through regulating the defense-associated protein metabolism, thus boosting resistance to pathogens and pests. Additionally, this review highlights the potential of integrating cullin-based strategies with advanced biological tools, such as CRISPR/Cas9-mediated genome editing, genetic engineering, marker-associated selections, gene overexpression, and gene knockout, to achieve precise modifications for crop improvement and sustainable agriculture, with the promise of creating resilient, high-yielding, and environmentally friendly crop varieties.