Three-wave mixing spectroscopy of chiral molecules, which exist in left-handed and right-
handed conformations, allows for enantioselective population transfer despite random 
orientation of the molecules. This is based on constructive interference of the three-photon 
pathways for one enantiomer and the destructive one for the other. We prove here that 
three mutually orthogonal polarization directions are required to this end. Two different 
dynamical regimes exist to realize enantioselective population transfer, and we show that 
they correspond to different phase conditions in the three-wave mixing. We find the 
excitation scheme used in current rotational three-wave mixing experiments of chiral 
molecules with C1 symmetry to be close to optimal and discuss the prospects for 
rovibrational three-wave mixing experiments of axially chiral molecules. Our comprehensive 
study allows us to clarify earlier misconceptions in the literature.