Given the modern background of economic globalization, regional economic integration, new global economic development trends caused by modern technological reforms, the Belt and Road initiative, and the Guangdong-Hong Kong-Macao Greater Bay Area development strategy, there is a growing sense of urgency, necessity, and practical significance in achieving the joint development of the Guangdong-Hong Kong-Macao region. This requires an in-depth understanding and accurate grasp of the key scientific issues and important topics related to this task. This article argues that research related to the joint development of the Guangdong-Hong Kong-Macau region must be based on a regionally unified theoretical framework, "global-local" scale theory, and regional spatial interaction theory as its theoretical basis. In this regard, key scientific issues include the study of the theory of regional linkages of scale in Guangdong, Hong Kong, and Macau under the "One Country, Two Systems" framework, and the exploration of mechanisms, factors, models, and pathways governing linkages in the Guangdong-Hong Kong-Macau region. In so doing, this article proposes four important topics that can be considered with regard to the joint development of the Guangdong-Hong Kong-Macau region: (1) Research and exploration of unification/coordination theory in the Guangdong-Hong Kong-Macau region under the "One Country, Two Systems" framework; (2) Research related to the location and role of the Guangdong-Hong Kong-Macau region; (3) Research related to the multi-scale and multi-agent impact mechanisms and models for the linkages between Guangdong, Hong Kong, and Macau; (4) Research related to implementation pathways for the unified development of Guangdong, Hong Kong, and Macau.