This article examines the hydrodynamic stability of various homogeneous three-dimensional flow topologies. The influence of inertial and pressure effects on the stability of flows undergoing strain, rotation, convergence, divergence, and swirl are isolated. In marked contrast to two-dimensional topologies, for three-dimensional flows the inertial effects are always destabilizing, whereas pressure effects are always stabilizing. In streamline topologies with a negative velocity-gradient third invariant, inertial effects prevail leading to instability. Vortex-stretching is identified as the underlying instability mechanism. In flows with positive velocity-gradient third derivative, pressure overcomes inertial effects to stabilize the flow.