Rare earth-doped upconversion luminescence nanomaterials have received considerable attention from researchers due to their great potential for applications in many fields such as information security, biomedicine, optical fiber communication, digital displays, and energy. The recently-developed upconversion luminescence nanoparticles with orthogonal excitation-emission properties have attracted especially strong research interest because their distinct luminescence outputs can be dynamically modulated by switching the excitation conditions. The orthogonal luminescence properties further endow such nanocrystals with a set of new features and functionalities, which largely expands their potential applications. This review summarizes the progress in the development of orthogonal upconversion luminescence of rare earth ions, and provides a systematic discussion on design principles and construction strategies of orthogonal excitation-emission systems based on core-shell structures, as well as introduces their recent advances in various fields of applications including data storage, security anti-counterfeiting, digital displays, sensing, bioimaging and therapy. Furthermore, the prospective opportunities and challenges in the future research of orthogonal luminescence systems are also provided.