Heterotrimeric G proteins mediate myriads of cell functions including control of cancer cell proliferation and migration. The family of the Regulators of G protein Signaling (RGS) proteins, in turn, controls the activity of G proteins through the acceleration of GTPase activity of the alpha subunits of G proteins. Increasing evidence suggest that the expression of certain RGS proteins is changed dramatically in various cancers, and in some instances, the control of cancer cell proliferation or migration by RGS proteins has been demonstrated. We assessed if common trends might exist in the expression of various RGS proteins in several types of cancer by examining microarray data using the Oncomine database. We focused on the largest R4 sub-family of RGS proteins, containing RGS1, RGS2, RGS3, RGS4, RGS5, RGS8, RGS13, RGS16 and RGS18. This analysis suggests that a number (up to 6) of RGS transcripts are exclusively downregulated in certain cancers, while being exclusively upregulated in other cancer types. Furthermore, significant changes in the expression of certain RGS proteins trended toward the same direction across various cancers. To illustrate, RGS1 is largely upregulated, whereas RGS2 is downregulated in the majority of solid tumors, whereas RGS5 transcripts are greatly increased in eight subtypes of lymphoma with no reports of downregulation in hematological malignancies. Together, these data suggest that (i) RGS proteins may have a combined and cell-specific role in a control of cancer cell function, and (ii) a given RGS protein may regulate the progression of various cancers through a common mechanism.