Lexie Grey, long lost half-sister of Meredith, came to Seattle Grace as an intern and was assigned to Cristina Yang's team. The initial reunion of Meredith and Lexie was a bit rocky. Meredith believed that she could have had the nice upbringing Lexie had if Thatcher hadn't left her and her mother. Meredith did eventually sit down with Lexie and explain the circumstances surrounding her mother's death. The two half-sisters bonded over this and an inkling of a friendship started to kindle.

The first of Lexie's many relationships also started in her first year as well. She began a casual-sex relationship with Alex Karev, a colleague at Seattle Grace. The affair was doomed to fail from the beginning and it all blew up when she learned Alex still had feelings for Rebecca Pope.