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The exact nature of Sino-Tibetan relations during the Ming Dynasty (1368–1644) of China is unclear. Analysis of the relationship is further complicated by modern political conflicts, and the application of Westphalian sovereignty to a time when the concept did not exist. Some Mainland Chinese scholars, such as Wang Jiawei & Nyima Gyaincain, assert that the Ming Dynasty had unquestioned sovereignty over Tibet, pointing to the Ming court's issuing of various titles to Tibetan leaders, Tibetans' full acceptance of these titles, and a renewal process for successors of these titles that involved traveling to the Ming capital. Scholars within the PRC also argue that Tibet has been an integral part of China since the 13th century, thus a part of the Ming Empire. But most scholars outside the PRC, such as Turrell V. Wylie, Melvin C. Goldstein, and Helmut Hoffman, say that the relationship was one of suzerainty, that Ming titles were only nominal, that Tibet remained an independent region outside Ming control, and that it simply paid tribute until the reign of Jiajing (1521–1566), who ceased relations with Tibet.

Some scholars note that Tibetan leaders during the Ming frequently engaged in civil war and conducted their own foreign diplomacy with neighboring states such as Nepal. Some scholars underscore the commercial aspect of the Ming-Tibetan relationship, noting the Ming Dynasty's shortage of horses for warfare and thus the importance of the horse trade with Tibet. Others argue that the significant religious nature of the relationship of the Ming court with Tibetan lamas is underrepresented in modern scholarship. In hopes of reviving the unique relationship of the earlier Mongol leader Kublai Khan (r. 1260–1294) and his spiritual superior Drogön Chögyal Phagpa (1235–1280) of the Tibetan Sakya sect, the Ming Chinese Yongle Emperor (r. 1402–1424) made a concerted effort to build a secular and religious alliance with Deshin Shekpa (1384–1415), the Karmapa of the Tibetan Karma Kagyu. However, Yongle's attempts were unsuccessful.