The year 2019 marked the centenary of the academic field of International Relations (IR) and called for a serious and thorough assessment of its past achievements and failures, as well as the challenges that lay ahead. IR seems to be experiencing an existential crisis quite unlike anything else in its hundred-year history and it is in an ongoing search for its very “soul”. This paper is trying to offer some reflections on the theoretical and meta-theoretical challenges that lay ahead for the field. In so doing, it first discusses three theoretical challenges: a) the question of policy relevance and of the socio-political utility of IR, b) the quest for a science with predictive power, and c) the widespread epistemic fatigue with grand-theories and the rise of analytical eclecticism. It then proceeds by offering reflections on three categories among the meta-theoretical challenges: a) the historiographical challenges, which refer to distortions of the conventional historiographical narrative for the evolution of the field and consequently to the distorted prevailing disciplinary self-image, b) philosophical challenges referring to the turn of IR to philosophy of science in an attempt to seek scientific credentials and philosophical legitimization for its knowledge claims, and c) to sociological challenges referring to the power-knowledge nexus and associated geographical and gender disparities in the global production of IR knowledge.