In 1976 she was appointed by congress to head the NIH's Commission for the Control of Huntington's Disease and its Consequences. In 1985 she joined the College of Physicians and Surgeons at Columbia University.

In 1979 Wexler's research led her to Lake Maracaibo in Venezuela, where she studied a community which had a high incidence of Huntington's disease. Wexler kept medical records, took blood and skin samples, and charted the transmission of the disease within families. Wexler sent the samples she collected to geneticist James Gusella at Massachusetts General Hospital, who used the blood samples to conduct a study to locate the gene—the first such genetic mapping of a disease. Gusella eventually discovered a deoxyribonucleic acid (DNA) marker close to the Huntington's gene. Based on this study, Gusella introduced a test that was ninety-six percent accurate in detecting whether an individual bears the Huntington's gene. Because there was still no cure for the Huntington's disease, the test proved to be controversial, raising many issues involving patient rights, childbearing decisions, and discrimination by employers and insurance companies. In her interviews and writings Wexler has stressed the importance of keeping such genetic information confidential.

In 1993 the Huntington's gene was identified through research based on the Venezuelan blood samples and the work of the Huntington's Disease Collaborative Research Group. In October, 1993, Wexler received an Albert Lasker Public Service Award for her role in this effort. In addition, she has served as an advisor on social and medical ethics issues to the Human Genome Project—a massive international effort to map and identify the approximately 100, 000 genes in the human body. Wexler also has assumed directorship of the Hereditary Disease Foundation founded by her father, to which she donated the honorarium that accompanied the Lasker Award.

As a pioneer in the field of geriatric care management, Wexler was a founding member of the National Association of Professional Geriatric Care Managers. Sher served on the organization's first National Board of Directors, as well as the association's first standards committee. She serves as director of Gerontology Associates, Alzheimer's Case Management Professional Placement Services in Los Angeles and is on the staffs of UCLA Neuropsychiatric Institute, Encino-Tarzana Regional Medical Center, and Northridge Hospital.