This chapter provides an overview of the context and challenges in the postwar era with respect to the dynamics of domination and resistance between the North and the South. It provides a perspective rooted in Marxian political economy, on the changing economic-structural correlates, from the early postwar period to the onset of Neoliberalism in the early 1970s. It is argued that, especially in the latter period, it became increasingly evident that the prospects of charting out relatively autonomous economic development in the newly decolonized countries, or more generally in the South, confronted very powerful obstacles and challenges. The chapter provides a conceptual/empirical mapping of the South and the North at the current juncture, before turning to the prospects of solidarities and the underlying major challenges. It argues that solidarity requires that the end of imperialist wars and sanctions be given priority, and that the right to national self-determination and autonomous development be respected. These are the preconditions for charting a new course, with a view to reverse privatization and commodification of public goods and nature and to deliver essential goods and services for the social reproduction of the masses of working people perpetually trapped in multiple vulnerabilities. Humanity’s common issues can be basis for solidarity, as both the North and the South grapple with the consequences of a capitalist system that prioritizes profit over people.