This paper reviews the first 25 years of how the “One Country, Two Systems” policy, tangibly and intangibly, transformed the Hong Kong-Mainland China border from the Hong Kong side. To address the border’s complexity, the author applied interdisciplinary research to obtain a holistic picture of the border, assimilating expertise from urban regeneration, ekistics, economics, geopolitics, and biology. Based on 25 years of data regarding Hong Kong’s border region, such as cross-border travel mobility based on economic status and geographical boundaries, demographical changes, and land use fluctuations, it is proven that all social development is subjected to humanity’s biological instinct for higher chances of survival, which is embodied by how governments limit cross-border travel freedom. It reveals genuine and engraved difficulties for the “two systems” to overcome, and disruptive institutional innovation is needed for the desired cross-border integration to transpire.