Wilhelm Ostwald, Ernst Mach, and Pierre Duhem are among the most prominent critics of atomism in the late 19th century. We review and analyze the arguments that these authors adduce to oppose the atomistic conception of matter. We show how these arguments arise from fundamental philosophical positions on the foundation of nature, the object of science and the role of metaphysics. We compare these philosophical positions. And we frame the critique of atomism in the more general epistemological problem of explanation to show the tension between explanation and experience, and its relation to metaphysics.