We identify the nuclear effects that modify the cross sections for open heavy flavor production in proton-nucleus and nucleus-nucleus collisions. In p+A reactions, we calculate and resum the coherent nuclear-enhanced power corrections from the final-state parton scattering in the medium. We find that single and double inclusive open charm production can be suppressed as much as the yield of neutral pions from dynamical high-twist shadowing. Effects of energy loss in p+A collisions are also investigated. These lead to significantly weaker transverse momentum dependence of the nuclear attenuation and give a sizable contribution to the forward rapidity hadron suppression. In A+A reactions we revisit the question of the measured large heavy flavor quenching at RHIC. We derive the collisional broadening of the heavy meson's transverse momentum and the distortion of its intrinsic light cone wave function. The medium-induced dissociation probability of heavy mesons is shown to be sensitive to the opacity of the quark-gluon plasma and the time dependence of its formation and evolution. In contrast to previous results on heavy quark modification, our approach predicts suppression of B-mesons comparable to that of D-mesons at transverse momenta as low as pT ~ 10 GeV. It allows for an improved description of the large attenuation of non-photonic electrons in central Au+Au reactions at RHIC. Preliminary results in the implementation of collisional and radiative energy loss in a Langevin simulation approach to heavy quark diffusion and attenuation are also presented.