Abstract. We develop the regularity theory for solutions to space-time nonlocal equations driven by fractional powers of the heat operatorThis nonlocal equation of order s in time and 2s in space arises in Nonlinear Elasticity, Semipermeable Membranes, Continuous Time Random Walks and Mathematical Biology. It plays for spacetime nonlocal equations like the generalized master equation the same role as the fractional Laplacian for nonlocal in space equations. We obtain a pointwise integro-differential formula for (∂t−∆) s u(t, x) and parabolic maximum principles. A novel extension problem to characterize this nonlocal equation with a local degenerate parabolic equation is proved. We show parabolic interior and boundary Harnack inequalities, and an Almgrem-type monotonicity formula. Hölder and Schauder estimates for the space-time Poisson problem are deduced using a new characterization of parabolic Hölder spaces. Our methods involve the parabolic language of semigroups and the Cauchy Integral Theorem, which are original to define the fractional powers of ∂t − ∆. Though we mainly focus in the equation (∂t − ∆) s u = f , applications of our ideas to variable coefficients, discrete Laplacians and Riemannian manifolds are stressed out.