Along with Carl Vogel, Pickering discovered the first spectroscopic binary stars. He wrote Elements of Physical Manipulations (2 vol., 1873–76).
He served as director of Harvard College Observatory, where he made great leaps forward in the gathering of stellar spectra through the use of photography. At Harvard, he recruited many women to work for him, including Annie Jump Cannon, Henrietta Swan Leavitt, and Antonia Maury. These women, who came to be known as "Pickering's Harem" by the scientific community, made several important discoveries at HCO.