A technique and system are provided for compression of tomosynthesis imaging data. In an embodiment of the present technique, tomosynthesis imaging data may be compressed by processing a stack of tomosynthesis images such that differences between some or all of the images or estimates of the images are encoded. In another embodiment of the present technique, tomosynthesis imaging data may be compressed by differentially compressing two or more regions within the one or more tomosynthesis imaging datasets. In addition, there is provided tangible, machine readable media, with code executable to perform the acts of obtaining one or more tomosynthesis imaging datasets and compressing the one or more tomosynthesis imaging datasets using one or more compression algorithms.