A series of clinical questions and stated hypotheses suggested in the pre-1960s regarding the differences between stimuli of occlusion and diffusion are presented (Part I) and are answered and confirmed by a series of experiments and data in animals and humans. A diffusion stimulus is extremely destructive to development of the acuity system in an eye per se (as well as producing myopia), and a unilateral diffusion stimulus is also destructive to development of the binocular system. Real occlusion is a no-stimulus condition that can be used to preserve normal acuity and binocular development, and as a delay tactic to successfully counteract the detrimental effect of diffusion. Binocular input differences (especially if one is a diffusion stimulus) are a major cause of strabismus in both the immature and mature binocular systems. The hypothesis was proposed that preoperative full-time alternate occlusion in infantile esotropia enhanced the binocularity outcome (for which supportive experimental data in animals and humans from our laboratories are discussed in Part III). Animal experiments during the 1960s and 1970s are reviewed relative to the confusion and conflict generated (Part II), since many of these experiments were based on the false assumptions that the unilateral eyelid closure model was a no-stimulus condition (because of the small amount of light transmitted). In fact, it was a worst-case severe stimulus with both monocular and binocular detrimental consequences. And the unilateral eyelid closure model usually produced either undetected or ignored strabismus in the animal experiments, with such strabismus severely compounding the detrimental effects of the eyelid closure model. Further confusion was added by the amblyopia therapeutic model in animals of "reverse eyelid occlusion" (which was really reverse diffusion) and which the author maintains was a gross distortion of the clinician's real occlusive patch over the better eye in the therapy of amblyopia of the poorer eye. These confusions and conflicts were at variance with long-standing clinical percepts. Part III provides data from the series of animal and human experiments from our laboratories at Smith-Kettlewell Eye Research Institute, which clarify the confusion and conflicts of some of the animal experiments described. Our data support the original hypotheses (Part I) enabling the clinician to use occlusion measures in selected patients to expand the therapeutic timing options and to improve visual outcomes. Binocular system outcomes are shown to be improved by our recent data in animal and human experiments, thus supporting the beneficial sensory effects of preoperative full-time alternate occlusion regimes in infantile esotropia.