For 25 years now, there has been a serious attempt to get at the fundamental cause(s) of dyslexia in our laboratory. A great deal of research has been carried out on the psychological and brain underpinnings of the linguistic dysfunctions seen in dyslexia, but attempts to get at its cause have been limited. Initially, observations were made on the brains of persons with dyslexia who had died and their brains donated for research. These observations were modeled in animal models in order to better understand the full extent of anatomical and developmental brain characteristics. More recently, models have begun to employ genetic manipulations in order to close the gap between genes, brain, and behavior. In this article based on a lecture given in memory of Dr. Norman Geschwind to the International Dyslexia Association assembly in Philadelphia in 2004, I outline the history of the research leading up to the most recent findings. These findings consist of experiments using methods that interfere with the function of DNA, using as constructs genes that have been implicated in dyslexia, which cause developmental problems of neuronal migration in rats, secondary brain changes in response to the migration problems, and abnormal processing of sounds.