In high TB- and HIV-burden settings, the two diseases reinforce each other and share common risk factors. Single, categorical services provided to persons with multiple, related risk factors miss opportunities to diagnose, treat, and prevent TB and/or HIV. Ethiopia is a high TB/HIV burden country that started implementing globally recommended collaborative TB/HIV activities in 2004, but several implementation challenges still remain. Both global and Ethiopian national guidelines recommend integrated approaches to tackle the dual burden of TB and HIV. It is also believed that an integrated, family based approach to TB and HIV care can remove access barriers, reduce delays in diagnosis, and improve management of TB among women, children, and other vulnerable groups. However, there is considerable variation across high disease-burden countries in terms of translating these recommendations into action. In Ethiopia, for example, TB and HIV clinics collaborate with each other through cross-referrals. Under ideal conditions, both TB and HIV patients should receive a full package of services in one place— an approach often referred to as “one-stop shop.” However, there are several barriers to implementing such an approach. To address these challenges, the USAID-funded Challenge TB (CTB) Project designed an innovative family-matrix-guided implementation approach in selected demonstration sites in Ethiopia. This demonstration project was implemented through a collaborative process within the framework of existing national guidelines under the direction of senior leadership from Amhara and Oromia regions and Dire Dawa and Harari city administrations.