This paper looks at interactions between Syriac Orthodox Christians in the Ottoman Empire and American missionaries with the American Board of Commissioners for Foreign Missions (ABCFM) in the second half of the nineteenth century. The last decade has seen a resurgence in scholarly interest in foreign missionaries to the Middle East. This paper continues and moves beyond that trend by extending the scope of analysis to the Syriac Orthodox community and to the understudied region known to contemporary missionaries as "Eastern Turkey," stretching approximately from Diyarbakir to Mosul. It furthermore relies as much on local sources as it does missionary sources. Using documents written in Garshuni (Arabic and Ottoman Turkish written in the Syriac script) from the Patriarchal archive of the Syriac Church in Mardin, I center the Syriac perspective in a field thus far dominated by the missionary perspective. A geographical concentration on Mardin also blurs the conventional historiographical boundary between Anatolia and the Arab world. I supplement these sources with the personal papers of missionary William Frederic Williams, held in the archive of the Divinity School at Yale University. The untold story that emerges is that of American missionaries in the backwaters of the empire (from the perspective of the ABCFM, which was more concerned with the Holy Land) struggling with limited financial resources to meet the demands of evangelizing in an area as ethnically, religiously, and, most importantly, linguistically diverse as Eastern Turkey. Their uniquely challenging evangelical work required they depart from traditional missionary methods and rely more heavily on the expertise—social and political as well as linguistic—of the locals. The unexpected alliances that developed demonstrate the fluidity of local-foreigner relations in this diverse landscape while calling into question the cohesiveness of the American missionary enterprise itself. Making use of local documents that reveal the quotidian life of the Syriac Christians, this paper furthermore contributes to scholarship on Ottoman religious communities. It does so by illuminating and giving texture to a widely dispersed but tight-knit community simultaneously advocating for itself and negotiating its boundaries amidst constant interactions not only with other local communities—Christian and Muslim, Armenian and Kurdish, and otherwise—but with American and British missionaries as well.