Plants viruses spread throughout their hosts using a number of pathways, the most common being movement cell to cell through plasmodesmata (PD), unique intercellular organelles of the plant kingdom, and between organs by means of the vascular system. Pioneering studies on plant viruses revealed that PD allow the cell-to-cell trafficking of virally encoded proteins, termed the movement proteins (MPs). This non-cell-autonomous protein (NCAP) pathway is similarly employed by the host to traffic macromolecules. Viral MPs bind RNA/DNA in a sequence nonspecific manner to form nucleoprotein complexes (NPC). Host proteins are then involved in the delivery of MPs and NPC to the PD orifice, and a role for the cytoskeleton has been implicated. Trafficking of NCAPs through the PD structure involves three steps in which the MP: (a) interacts with a putative PD docking complex, (b) induces dilation in the PD microchannels, and (c) binds to an internal translocation system for delivery into the neighboring cytoplasm. Viral genera that use this NCAP pathway have evolved a combination of a MP and ancillary proteins that work in concert to enable the formation of a stable NPC that can compete with endogenous NCAPs for the PD trafficking machinery. Incompatible MP-host protein interactions may underlie observed tissue tropisms and restricted infection domains. These pivotal discoveries are discussed in terms of the need to develop a more comprehensive understanding of the (a) three-dimensional structure of MPs, (b) PD supramolecular complex, and (c) host proteins involved in this cell-to-cell trafficking process.