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The idea that small RNAs ingested from plant-based foods could have biological effects in humans and other mammals is currently an issue of considerable interest. It has long been known that ingested RNA from food sources is taken up by the digestive system in nematodes and insects and can control the expression of genes in those organisms. A recent report has raised the interesting possibility that a similar phenomenon occurs in humans and other mammals. This work has generated excitement because it raises the possibility of bioengineering edible plants to produce therapeutic miRNAs that could then be delivered to affected tissues by ingestion. However, it has also generated controversy, and several groups have challenged the finding. We addressed this controversy in an experiment designed to both detect a therapeutic effect of ingested miRNAs and to demonstrate their uptake in a mouse model for colon cancer. Our results indicate that tumor suppressor miRNAs designed to mimic small RNAs produced in plants were taken up by the mouse digestive tract upon ingestion and were functional as evidenced by reduction in tumor burden. Our results support the original finding that endogenous plant miRNAs are taken up by the mammalian digestive tract and function to target mammalian genes, raising the intriguing prospect of using edible plants engineered to produce mammalian tumor suppressor miRNAs as an effective, nontoxic, and inexpensive chemopreventive strategy in humans.