This presentation focuses on research in the Mississippi Delta that illustrates the advantages of crop rotation with cotton and how yields can be increased over a long period without increasing inputs. Although yields of cotton following corn are 9–20% higher than yields of continuous cotton, producers see problems in some years as environmental conditions such as rainfall negatively impact good cotton growth. While the research has been conducted in the U.S. Mid-South, the implications reach across the Cotton Belt. The presentation also summarizes the first 12 years of the Centennial Rotation (established in 2004), which continues to provide valuable information on multicrop rotation sequences, including cotton, corn, and soybean. Long-term research is valuable in understanding the overall impact of crop rotation. The advantages outweigh the disadvantages, but environmental extremes can change even the best intentions in crop rotations. One of the strong points in support of research underway at Stoneville, Mississippi, is replication and the fact that every crop in a rotation sequence is grown each year. Thus, shifts in market prices, which can vary depending on the year, can be evaluated in the economic analysis.