Many lessons in long-term cropping systems experiments are learned from practical experience. I have conducted large-scale, long-term, multidisciplinary dryland and irrigated cropping systems experiments with numerous colleagues at university and government research stations and in farmers' fields in the USA and in developing countries for 25 years. Several practical lessons learned through the years are outlined in this short commentary. While some of these lessons learned may be intrinsically obvious, results of many cropping systems experiments have not been published in scientific journals due to fatal flaws in experimental design, improper transitioning between phases of the experiment and many other reasons. Ongoing active support by stakeholders is critical to maintain funding for long-term cropping systems studies. Problems and unexpected challenges will occur, but scientists can often parlay these into opportunities for discovery and testing of new hypotheses. Better understanding and advancement of stable, profitable and sustainable cropping systems will be critical for feeding the world's projected 10 billion people by the mid-21st century.