Compared to other vertebrates, even including lampreys and hagfishes in some respects, salamanders exhibit a relatively simple organization of brain and sense organs which is illustrated here using the visual system as an example. The greatest simplicity is found in the bolitoglossine salamanders, yet all bolitoglossines possess highly projectile tongues and rely on vision for survival; furthermore, some species are agile and acrobatic. The unusual features of the visual system of salamanders include small numbers of large neurons, a low degree of morphological differentiation among neurons, a small proportion of myelinated axons in the optic nerve, and an optic tectum consisting essentially of a periventricular cellular layer and a superficial fiber layer. Similar features are found throughout the central nervous system of salamanders and in the lateral line, auditory and olfactory systems as well. Phylogenetic analysis shows that the most parsimonious interpretation of these data is that the simple organization of the brain and sense organs of salamanders was derived secondarily from a more complex ancestral state. We hypothesize that increased genome size has led to simplification of the nervous system in salamanders. Increased genome size appears to have had profound effects on neural development in salamanders, leading to paedomorphosis, the retention of juvenile or even embryonic characteristics into adulthood. In particular, large genome size is associated with large cell size and reduced rates of cell proliferation, migration and differentiation. Secondary simplification has constrained the function of the salamanders'' visual system, primarily by increasing cell size and decreasing cell numbers. However, it also has provided an opportunity for the evolution of compensating mechanisms, which have helped to restore or even enhance visual function. Most apparent among the compensatory mechanisms of bolitoglossine salamanders is the presence of well developed ipsilateral retinotectal projections, which apparently enhance depth perception. It is difficult to explain the unusual history of the nervous system in salamanders solely in terms of natural selection and adaptation. Increasing genome size through selfish replication appears to have played a major role in the evolution of salamander brains by imposing functional constraints as well as creating opportunities for overcoming them.