This paper outlines the fundamental issues that will determine whether or not the Millennium Development Goals (MDGs) can be achieved. The paper argues that such issues as gender inequity, the situation of fragile states, the humanitarian-development divide, and economic growth may not be present in every MDG, but will influence progress on every one of the goals. The lack of progress on the MDG targets for sanitation and maternal mortality, for example, may be rooted in gender discrimination and policy failings that are not fully addressed by the MDGs themselves. The Paper calls on all actors to work with, rather than against, the grain of southern realities, in efforts to achieve the MDGs.