Membrane channels for water and small nonionic solutes are required for osmoregulation in bacteria, plants, and animals. Aquaporin-1, the water channel of human erythrocytes, is the first channel demonstrated to conduct water, by expression in Xenopus oocytes. Phylogenetic analyses reveal the existence of two clusters of subfamilies, the aquaporins (AQPs) and glycerol facilitators (GLPs). Sequence-based structure prediction provided a model comprising six membrane-spanning helices, while sequence analyses suggested strategic residues that are important for structure and function. The surface topography of several AQPs has been mapped by atomic force microscopy, revealing different features that correlate with differences in the loops connecting transmembrane helices. The 3D structures of AQP1 and GlpF have been determined by electron cryomicroscopy. The 3.8-A density map allowed the first atomic model of AQP1 to be built, taking into account data from sequence analyses. This model provides some insight into the permeation of water through a channel that blocks the passage of protons. GIpF has been resolved to 6.9 A, revealing helices that are similar to those of AQP1. Homology modeling shows the channel region of these distant aquaglyceroporins to be similar, as confirmed by the 2.2-A structure of GlpF from X-ray crystallography.