The increased number of development cooperation and sustainable agriculture partnerships brings with it new challenges for professionals who are asked to facilitate these partnering processes. In this article we shed more light on the world of development cooperation and we explore questions that facilitators working with North-South partnerships face. The main research questions are: What are the distinguishing characteristics of North-South partnership dynamics; what insights and lessons can we draw from the management of these partnerships, and what recommendations or advice can we offer to those facilitating such partnerships? On the basis of a deductive research process we reveal a number of characteristics that mark the process of building partnerships within the context of development cooperation. Through two cases of sustainable agriculture partnerships—biological cotton and responsible soy—we discuss how professionals confront these specific characteristics and how they address these. The material from the two cases was made more complete by drawing on other experiences and relevant literature. The revealed characteristics creating challenges for professionals facilitating partnerships are the following: ideology and values; politically loaded relationships; unilateral financial dependence; cultural and physical distance; and fragile social trust. We end with some essential operational guidelines for professionals managing or advising partnerships. As partnerships in development cooperation are becoming ever more important, there is a need for more professionalization. However, few studies have paid attention to the challenges professionals face and the way they can deal with them.