Supplementation with the crucifer-derived phytochemicals indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) has been an area of active interest due to their role in estrogen metabolism. This review addresses the debate about which cruciferous compound to use clinically by evaluating their efficacy and safety. Significantly more clinical trials are available for I3C than for DIM. I3C leads to beneficial shifts in hormone markers, and limited evidence suggests that DIM may result in a similar effect. More research in humans is needed to further address whether DIM poses any safety risk. Current data do not suggest that DIM provides enhanced clinical benefits over I3C.