We provide a comprehensive, up-to-date analysis of possible New Physics contributions to the mass difference ∆M_D in D^0- D ̅^0 mixing. We consider the most general low energy effective Hamiltonian and include leading order QCD running of effective operators. We then explore an extensive list of possible New Physics models that can generate these operators, which we organize as including Extra Fermions, Extra Gauge Bosons, Extra Scalars, Extra Space Dimensions and Extra Symmetries. For each model we place restrictions on the allowed parameter space using the recent evidence for observation of D meson mixing. In many scenarios, we find strong constraints that surpass those from other search techniques and provide an important test of flavor changing neutral currents in the up-quark sector. We also review the recent BaBar and Belle findings, and describe the current status of the Standard Model predictions of D^0- D ̅^0 mixing.