He is the Frances and Albert Piansky Endowed Chair and Distinguished Professor of Pathology and Laboratory Medicine and of Biological Chemistry at the University of California, Los Angeles.

[1] Tontonoz's laboratory focuses on studying regulatory pathways involved in cholesterol, fatty acid, and phospholipid metabolism, contributing to uncovering fundamental mechanisms through which animals maintain cellular and whole-body lipid homeostasis.

His group has clarified pathways governing lipid uptake, transport, and efflux, demonstrating their impact on the function of immune cells and metabolic tissues in both physiological and pathological conditions.

Following this, from 1996 to 1999, his postdoctoral work with Ronald M. Evans furthered his research in lipid signaling, connecting nuclear receptor pathways to macrophage biology and atherosclerosis.

[11] Tontonoz joined UCLA's faculty in 1999 as an assistant professor in the Department of Pathology and Laboratory Medicine, concurrently assuming the role of Investigator at the Howard Hughes Medical Institute in 2000, where he served until 2017.

[17] His group moved on to analyze a range of LXR target genes that collaborate systematically to facilitate cellular cholesterol removal, and to demonstrate the significance of these pathways for metabolic homeostasis in vivo.

[32][33] In 2018, Tontonoz addressed the issue of cholesterol transport between the plasma membrane and the ER by discovering a family of three previously unidentified proteins, which he named Asters, serving as innovative intracellular sterol carriers.