In this chapter, I present the most important approaches to causation and causal explanation that have deeply influenced the new mechanical philosophy (NMP). I start by discussing Carl Hempel’s theory of explanation and I emphasize its limits. After that, I focus on Wesley Salmon’s mechanistic theory of causation. On the one hand, Salmon has taken Hume’s challenge seriously by looking for a physical connection between cause and effect. On the other, he strongly criticizes the Hempelian account of explanation by opting for an ontic account of scientific explanation. Not neglecting the importance of Salmon’s contribution, I argue that the NMP cannot be properly understood without assessing the role of the manipulationist approaches to causation—an agency and interventionist one. A general idea about causation within these approaches is that causal relations are potentially exploitable for purposes of manipulation and control. Although philosophers of causation like Peter Menzies, Huw Price, and James Woodward did not consider themselves mechanists, I show how their contribution has added important aspects to the mechanistic view on causation and explanation.