Amblyopia is the condition in which reduced visual function exists despite full optical correction and an absence of observable ocular pathology. Investigation of the underlying neurology of this condition began in earnest around 40 years ago with the pioneering studies conducted by Hubel and Wiesel. Their early work on the impact of monocular deprivation and strabismus initiated what is now a rapidly developing field of cortical plasticity research. Although the monocular deprivation paradigm originated by Hubel and Wiesel remains a key experimental manipulation in studies of cortical plasticity, somewhat ironically, the neurology underlying the human conditions of strabismus and amblyopia that motivated this early work remains elusive. In this review, the authors combine contemporary research on plasticity and development with data from human and animal investigations of amblyopic populations to assess what is known and to reexamine some of the key assumptions about human amblyopia.