He received the Nobel Prize in Physiology or Medicine in 1985, along with fellow University of Texas Southwestern researcher, Michael Brown, for their studies regarding cholesterol.

[7] Frequently mentioned as a candidate for nationally prominent positions in scientific administration, Goldstein, like his colleague Michael Brown, chose to continue hands-on research.

[8][9] In 1993, their postdoctoral trainees, Wang Xiaodong and Michael Briggs, purified the Sterol Regulatory Element-Binding Proteins (SREBPs), a family of membrane-bound transcription factors.

Since 1993, Goldstein, Brown, and their colleagues have described the unexpectedly complex machinery that proteolytically releases the SREBPs from membranes, thus allowing their migration to the nucleus where they activate all the genes involved in the synthesis of cholesterol and fatty acids.

The machinery for generating active SREBPs is tightly regulated by a negative feedback mechanism, which explains how cells maintain the necessary levels of fats and cholesterol in the face of varying environmental circumstances.

[23] Since 2000, Goldstein has authored a series of essays on the deep relationship between art and science that appear in the annual Nature Medicine supplement that accompanies the Lasker Awards.