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 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.