The paper advances a ‘neo-federalist’ perspective to analyze the European multilevel system for the protection of fundamental rights. This perspective fits within the theoretical prism of constitutional pluralism but rejects the allure of a sui generis approach in favour of the analytical and heuristic virtues of the comparative methodology. By rediscovering the pluralist tradition of federalism of the United States of America and Switzerland, the paper claims that the European human rights architecture can be compared with the arrangements for the protection of fundamental rights in force in those two constitutional systems, and that, when put in comparative context, it can be better understood. In this light, the paper argues that two major challenges can be currently identified in the European system – ineffectiveness and inconsistency, provides several empirical examples to highlight them, and examines how the legal transformations taking place in Europe or other proposals for policy reforms might address them.