In 2012 Medine signed with the Creative Artists Agency, an entertainment talent agency headquartered in Los Angeles, California. In 2016 Medine launched MR by Man Repeller, a line of loafers, flats, metallic booties, and heels exclusive to Net-a-Porter which embodied her not too serious and irreverent style. MR by Man Repeller was followed by Medine's eponymous shoe brand Leandra Medine, which is sold at Barneys NY, Harvey Nichols, and The Webster.
She and Cohen were wed in June 2012. They live in the East Village. In a December 6, 2016, ManRepeller article, Medine revealed she had suffered a miscarriage. In the December 16, 2016, episode of her podcast, she gave more details about the experience.