Richard Pestell helped define the complex functions of the cyclin D1 oncogene, an important regulator of human cancer, identifying the requirement for cyclin D1 in breast cancer growth in animals, cited in clinical trials that led to FDA approval of CDK inhibitors. His laboratory identified key domains mediating non-canonical functions of cyclin D1, including transcription factor activity. He demonstrated the role of cyclin D1 in the regulation of glycolysis and mitochondrial biogenesis, potentially explaining the observation of altered sugar metabolism in cancers, which is now beginning to be exploited for cancer therapy. The Pestell laboratory also demonstrated cyclin D1 governs microRNA expression (immunoMirs) and processing via Dicer, cellular migration, and DNA damage repair. 

His laboratory discovered nuclear receptors undergo post-translational modification by acetylation, a process that is conserved between evolutionarily related receptors, including orphan nuclear receptors, to govern diverse functions, including contact-independent growth and hormonal responses.

His group was the first to show a vital role for the G-protein coupled receptor CCR5 in tumor growth and metastasis and the role of CCR5 inhibitor therapy in treatment of cancers, currently in clinical trials.