Throughout chromatographic method development, challenges often arise when peaks elute with the void volume, co-elute with each other, or do not elute at all. In these cases, it is beneficial to evaluate and/or develop orthogonal separation methods. For the last two decades, researchers have developed alternative approaches to method development. The focus changed from applying different chromatographic methods to evaluate impurity methods. Several groups worked to develop a system of comparing reversed-phase columns that ultimately came to be called the “Hydrophobic Subtraction Theory”. Separation techniques, modes of chromatography, and stationary phase material all can be orthogonal. Many models for characterizing orthogonality can be studied and used to make decisions on screening column sets for method development. At the end of the day, using the tools and maps described herein can only guide educated guesses on column orthogonality; it is up to the practitioner to find the right column for the job.