Known for most of its history as the "Harvard-Smithsonian Center for Astrophysics", the CfA rebranded in 2018 to its current name in an effort to reflect its unique status as a joint collaboration between Harvard University and the Smithsonian Institution.

[3] Charles Greeley Abbot was named SAO's first director, and the observatory operated solar telescopes to take daily measurements of the Sun's intensity in different regions of the optical electromagnetic spectrum.

Following the launch of Sputnik (the world's first human-made satellite) in 1957, SAO accepted a national challenge[5] to create a worldwide satellite-tracking network, collaborating with the United States Air Force on Project Space Track.

[6] For its first four years of operation, the observatory was situated[7] at the Dana-Palmer House (where Bond also resided) near Harvard Yard, and consisted of little more than three small telescopes and an astronomical clock.

[6] In his 1840 book recounting the history of the college, then Harvard President Josiah Quincy III noted that "there is wanted a reflecting telescope equatorially mounted".

[6] This telescope, the 15-inch "Great Refractor", opened seven years later (in 1847) at the top of Observatory Hill in Cambridge (where it still exists today, housed in the oldest of the CfA's complex of buildings).

Under the directorship of Edward Charles Pickering from 1877 to 1919, the observatory became the world's major producer of stellar spectra and magnitudes, established an observing station in Peru,[8] and applied mass-production methods to the analysis of data.

These "Computers" included Williamina Fleming, Annie Jump Cannon, Henrietta Swan Leavitt, Florence Cushman and Antonia Maury, all widely recognized today as major figures in scientific history.

[9] Henrietta Swan Leavitt, for example, discovered the so-called period-luminosity relation for Classical Cepheid variable stars,[10] establishing the first major "standard candle" with which to measure the distance to galaxies.

[11] Between Shapley's tenure and the formation of the CfA, the observatory was directed by Donald H. Menzel and then Leo Goldberg, both of whom maintained widely recognized programs in solar and stellar astrophysics.

That same year, a new astronomical journal, the CfA Preprint Series was created, and a CfA/SAO instrument flying aboard Skylab discovered coronal holes on the Sun.

Riccardo Giacconi, regarded as the "father of X-ray astronomy", founded the High Energy Astrophysics Division within the new CfA by moving most of his research group (then at American Sciences and Engineering) to SAO in 1973.

[14] The 1980s also saw the CfA play a distinct role in the history of computer science and the internet: in 1986, SAO started developing SAOImage, one of the world's first X11-based applications made publicly available (its successor, DS9, remains the most widely used astronomical FITS image viewer worldwide).

During this time, scientists and software developers at the CfA also began work on what would become the Astrophysics Data System (ADS), one of the world's first online databases of research papers.

[16] Research across the CfA is organized into six divisions and seven research centers: The CfA is also host to the Harvard University Department of Astronomy, large central engineering and computation facilities, the Science Education Department, the John G. Wolbach Library, the world's largest database of astronomy and physics papers (ADS), and the world's largest collection of astronomical photographic plates.