Embryonic stem cells (ESCs) hold great potential for therapeutic regeneration and repair in many diseases. However, many challenges remain before this can be translated into effective therapy. A principal and significant limit for outcome evaluations of clinical trials is to define the minimal graft population necessary for functional repair. Here we used a preclinical model for quantitative analysis of stem cell grafts, with wild-type ESC grafted into myelin mutant shiverer hosts, to determine minimum graft levels for therapeutic benefit. Using a timed motor function test we identified three groups, including recipients indistinguishable from nongrafted shiverer controls (time [t] = 20.1 +/- 1.1 seconds), mice with marginal improvement (t = 15.7 +/- 1 seconds), and mice with substantial phenotype rescue (t = 5.7 +/- 0.9 seconds). The motor function rescued chimeras also had a considerably extended life span (T(50) > 128 days) relative to both shiverer (T(50) = 108 days) and the nonrescued chimeras. Retrospective genotype analysis identified a strong correlation (r(2) = 0.85) between motor function and ESC-derived chimerism, with > 7% chimerism required for rescue in this murine model of central nervous system myelin pathology. These results establish the minimal levels of engraftment to anticipate therapeutic repair of a cell-autonomous defect by cell transplant therapy.