The voltage-gated proton channel (Hv1) of leukocytes, basophils, airway epithelium, and spermatozoa is extremely selective. Hv1 presents structural and functional similarities to the voltage-sensor domain (VSD) of voltage-gated potassium (Kv) and sodium (Nav) channels. Hv1 and the VSDs of Kv and Nav sense changes in membrane potentials and contain four α-helical segments as well as conserved arginine residues on the fourth helix. Although the electrophysiological features of Hv1 are well characterized, the molecular mechanism of proton conduction is unknown. This is largely because an experimentally-determined structure of Hv1 is not available. An alternative source of structural information is homology modeling, whereby a model of Hv1 can be constructed using the atomic structures of the VSDs of Kv and Nav as templates. However, since the sequence identity between Hv1 and templates is below 20%, a critical assessment of generated models is essential. Here we present a homology modeling-simulation strategy using alternative sequence alignments to construct, assess, and validate alternative homology models. Comparison of a range of structural properties between the models and templates is used to guide the selection of an optimal model for Hv1. This method represents a generalized strategy that can be applied to other membrane proteins that lack high sequence identity to their templates.