There are several important arguments in metaethics that rely on explanatory considerations. Gilbert Harman has presented a challenge to the existence of moral facts that depends on the claim that the best explanation of our moral beliefs does not involve moral facts. The Reliability Challenge against moral realism depends on the claim that moral realism is incompatible with there being a satisfying explanation of our reliability about moral truths. The purpose of this chapter is to examine these and related arguments. In particular, this chapter will discuss four kinds of arguments – Harman’s Challenge, evolutionary debunking arguments, irrelevant influence arguments, and the Reliability Challenge – understood as arguments against moral realism. The main goals of this chapter are (i) to articulate the strongest version of these arguments; (ii) to present and assess the central epistemological principles underlying these arguments; and (iii) to determine what a realist would have to do to adequately respond to these arguments.