RGS19 is a GTPase-activating protein that negatively regulates heterotrimeric G protein signaling by accelerating GTP hydrolysis on Gα subunits, preferentially targeting Gαi3, Gαi1, and Gαo isoforms. The protein is palmitoylated and membrane-anchored, localized to the plasma membrane and intracellular vesicles including clathrin-coated vesicles and the Golgi apparatus. Beyond its canonical role as a G protein regulator, RGS19 functions as a multifunctional oncogene in multiple cancer types. In hepatocellular carcinoma, RGS19 is upregulated and promotes tumor cell proliferation and metastasis through a positive feedback loop involving MYH9 protein stabilization and activation of β-catenin/c-Myc signaling 1. Similarly, in bladder cancer, RGS19 is significantly upregulated and linked to poor prognosis; RGS19 knockdown inhibits proliferation and migration while inducing apoptosis and autophagy, with mechanistic involvement of the cGMP-PKG signaling pathway 2. RGS19 also deregulates cell cycle progression in other contexts by upregulating cyclin D1/3 and Cdk6 while suppressing cell cycle inhibitors, and augments Akt phosphorylation 3. The gene undergoes alternative splicing to produce multiple tissue-specific isoforms 4, potentially contributing to functional diversity across tissues. These findings identify RGS19 as a promising therapeutic target in hepatocellular carcinoma and bladder cancer.