Silymarin (SM) is a popular botanical medicine with purported liver protective effects. SM displays multiple effects in animal models and in cell culture including prevention of liver disease, reduction of inflammation, oxidative stress, and proliferation. Despite a plethora of data indicating that SM impinges on multiple cellular signaling pathways important in inflammation and disease, no unifying mechanisms have been forwarded. To define how SM elicits so many biological effects, the current study presents the first comprehensive transcriptional profiling study of human hepatoma cells treated with SM. The intention of the study was to focus on the early transcriptional events that are associated with SM-induced inhibition of proliferation and inflammation. Collectively, the data demonstrate that SM causes a rapid transcriptional reprogramming of cells that initially manifests as energy stress and slowing of cellular metabolism, leading to inhibition of cell growth and inflammation.