The literature on agenda-setting powers of European institutions considers the Commission to be a primary actor in determining the European policy agenda, thanks to the both the formal and informal powers it holds. This paper demonstrates that despite the Commission’s formal powers of initiation and substantial technical resources within the policy making process, it is not the primary actor in shaping the EU’s policy process. Indeed, in the past decade, just forty per cent of all legislation adopted by the EU institutions were derived from the stated policy priorities of the Commission. Moreover, the Commission’s success in achieving its policy objectives are directly tied to the extent to which its preferences overlap with those of the other relevant legislative actors (the Council and the EP). The evolution of the European institutions under different treaties, and the subsequent changes in power dynamics, thus appear to have undermined the capacity of the Commission to effectively shape the European policy agenda. The decline in the agenda setting powers of the Commission has not been monotonic however; it has varied significantly both over time and across policy arenas. By identifying these variations in the agenda setting influence of the Commission vis-à-vis other actors over time, this paper utilizes two original datasets on Commission policy priorities and EU legislative output to tests the hypotheses that the Commission’s status as primary agenda-setter works better in regulatory and/or technical policy arenas in which other actors have less interest or knowledge. Through this analysis, our research investigates the extent to which we are witnessing a generalized loss of agenda-setting power for the Commission, or a case of institutional adaptation to changing circumstances as the Commission shifts its focus to more technical issue and frequently less politically salient areas.