Though antitrust cartel cases have received significant attention, the policy determinants and the political preferences that guide such enforcement remain understudied. We empirically examine the intertemporal shifts in U.S. cartel cases during the period 1969-2013. This period has seen substantive policy innovations with increasing penalties that are related to fines and jail terms. There appear to be four distinct cartel policy regimes: pre-1978, 1978-1992, 1993-2003, and 2004-2013. Our empirical estimates show significant variation in the number of cartel cases initiated and the penalties imposed across the policy regimes. The more recent regimes are characterized by far fewer cartel cases initiated, but with substantially higher penalties levied on firms and individuals. While effective deterrence is one explanation for these patterns, we are more inclined to conclude that U.S. cartel enforcement has seen an underlying shift away from focusing on smaller cartels to larger and multinational cartels. In terms of political effects, our results reveal no clear inter-political party effect, but there appear to be interesting intra-political party effects. We find that particular Presidencies matter for cartel enforcement, and variation across Presidential administrations led to marked shifts in the total number of cartel cases initiated. Overall, the shifts in the prosecution patterns portray changing policy priorities and a search for the optimal enforcement design to curtail one of the clearest sources of welfare loss, collusion.