The present disclosure relates to methodologies, systems and apparatus for controlling pressure in a CO2-based chromatography system. A first CO2 pump operates in constant flow mode and delivers CO2 to a chromatography column, and liquid modifier is introduced to the chromatography column according to a gradient. A second CO2 pump is disposed downstream of the column and operates in constant pressure mode to introduce CO2 into a flow stream at an output of the column. Liquid modifier is also introduced into the flow stream at the output of the column according to a reverse gradient compared to the gradient entering the chromatography column.