Spatial symmetries in crystals may be distinguished by whether they preserve the spatial origin. Here we study spatial symmetries that translate the origin by a fraction of the lattice period, and find that these non-symmorphic symmetries protect an exotic surface fermion whose dispersion relation is shaped like an hourglass; surface bands connect one hourglass to the next in an unbreakable zigzag pattern. These 'hourglass' fermions are formed in the large-gap insulators, KHgX (X = As, Sb, Bi), which we propose as the first material class whose band topology relies on non-symmorphic symmetries. Besides the hourglass fermion, another surface of KHgX manifests a three-dimensional generalization of the quantum spin Hall effect, which has previously been observed only in two-dimensional crystals. To describe the bulk topology of non-symmorphic crystals, we propose a non-Abelian generalization of the geometric theory of polarization. Our non-trivial topology originates from an inversion of the rotational quantum numbers, which we propose as a criterion in the search for topological materials.