Spiro-OMeTAD remains a prominent hole-transport material in perovskite and solid-state dye-sensitized solar cells. However, an understanding of its intrinsic hole-transport properties is still limited. Here, hole transport in spiro-OMeTAD is systematically characterized on the basis of the recently reported X-ray single-crystal data. An approach combining density functional theory calculations, tight-binding modeling, and kinetic Monte Carlo simulations are exploited to describe the key parameters governing hole transport and to investigate the transport mechanism and hole mobilities in the spiro-OMeTAD single crystal. The results provide insight into: (i) why an anisotropic hole-transport mechanism, with an upper range of intrinsic hole mobilities on the order of ~10−3 cm2/Vs, can be expected in the single crystal; and (ii) how detrimental factors, related to the presence of the spiro motif and of the 4,4′-dimethoxydiphenylamine substituents, limit the intrinsic hole mobilities of the system.