We use holographic duality to analyze the drag force on, and consequent energy loss of, a heavy quark moving through a strongly coupled conformal fluid with non-vanishing gradients in its velocity and temperature. We derive the general expression for the drag force to first order in the fluid gradients. Using this general expression, we show that a quark that is instantaneously at rest, relative to the fluid, in a fluid whose velocity is changing with time feels a nonzero force. And, we show that for a quark that is moving ultra-relativistically, the first order gradient “corrections” become larger than the zeroth order drag force, suggesting that the gradient expansion may be unreliable in this regime. We illustrate the importance of the fluid gradients for heavy quark energy loss by considering a fluid with one-dimensional boost invariant Bjorken expansion as well as the strongly coupled plasma created by colliding sheets of energy.