We report the control of guest release profiles by dialing-in desirable interactions between guest molecules and pores in metal–organic frameworks (MOFs). The interactions can be derived by the rate constants that were quantitatively correlated with the type of functional group and its proportion in the porous structure; thus the release of guest molecules can be predicted and programmed. Specifically, three probe molecules (ibuprofen, rhodamine B, and doxorubicin) were studied in a series of robust and mesoporous MOFs with multiple functional groups MIL-101­(Fe)-(NH2) x , MIL-101­(Fe)-(C4H4) x , and MIL-101­(Fe)-(C4H4) x (NH2)1–x . The release rate can be adjusted by 32-fold rhodamine from MIL-101­(Fe)-(NH2) x , and the time of release peak can be shifted by up to 12 days over a 40-day release period doxorubicin from MIL-101­(Fe)-(C4H4) x (NH2)1–x , which was not obtained in the physical mixture of the single component MOF counterparts nor in other porous materials. The corelease of two pro-drug molecules (ibuprofen and doxorubicin) was also achieved.