Elizabeth was born on 3 February 1821 in a house on Dicksons Street in Bristol, England, to Samuel Blackwell, a sugar refiner, and his wife Hannah (Lane) Blackwell. She had two older siblings, Anna and Marian, and would eventually have six younger siblings: Samuel (married Antoinette Brown), Henry (married Lucy Stone), Emily (third woman in the U.S. to get a medical degree), Sarah Ellen (a writer), John and George. Four maiden aunts, Barbara, Ann, Lucy and Mary, also lived with Blackwell during Blackwell's childhood.

Once again, through her sister Anna, Blackwell procured a job, this time teaching music at an academy in Asheville, North Carolina, with the goal of saving up the $3,000 necessary for her medical school expenses. In Asheville, Blackwell lodged with the respected Reverend John Dickson, who happened to have been a physician before he became a clergyman. Dickson approved of Blackwell's career aspirations and allowed her to use the medical books in his library to study. During this time, Blackwell soothed her own doubts about her choice and her loneliness with deep religious contemplation. She also renewed her antislavery interests, starting a slave Sunday school that was ultimately unsuccessful.  Dickson's school closed down soon after, and Blackwell moved to the residence of Reverend Dickson's brother, Samuel Henry Dickson, a prominent Charleston, physician. She started teaching in 1846 at a boarding school in Charleston run by a Mrs. Du Pre. With the help of Reverend Dickson's brother, Blackwell inquired into the possibility of medical study via letters, with no favorable responses. In 1847, Blackwell left Charleston for Philadelphia and New York, with the aim of personally investigating the opportunities for medical study. Blackwell's greatest wish was to be accepted into one of the Philadelphia medical schools.  My mind is fully made up. I have not the slightest hesitation on the subject; the thorough study of medicine, I am quite resolved to go through with. The horrors and disgusts I have no doubt of vanquishing. I have overcome stronger distastes than any that now remain, and feel fully equal to the contest. As to the opinion of people, I don't care one straw personally; though I take so much pains, as a matter of policy, to propitiate it, and shall always strive to do so; for I see continually how the highest good is eclipsed by the violent or disagreeable forms which contain it.  Upon reaching Philadelphia, Blackwell boarded with Dr. William Elder and studied anatomy privately with Dr. Jonathan M. Allen as she attempted to get her foot in the door at any medical school in Philadelphia. She was met with resistance almost everywhere. Most physicians recommended that she either go to Paris to study or that she take up a disguise as a man to study medicine. The main reasons offered for her rejection were that (1) she was a woman and therefore intellectually inferior, and (2) she might actually prove equal to the task, prove to be competition, and that she could not expect them to "furnish [her] with a stick to break our heads with". Out of desperation, she applied to twelve "country schools".

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