Single-crystal-to-single-crystal (SCSC) transformations represent some of the most fascinating phenomena in chemistry. They are not only intriguing from a basic science point of view but also provide a means to modify or tune the properties of the materials via the postsynthetic introduction of suitable guest molecules or organic functional groups into their structures. Here, we describe UCY-2, a new flexible Nd3+ metal-organic framework (MOF), which exhibits a unique capability to undergo a plethora of SCSC transformations with some of them being very uncommon. These structural alterations involve the replacement of coordinating solvent molecules of UCY-2 by terminally ligating solvents and organic ligands with multiple functional groups including -OH, -SH, -NH-, and -NH2 or their combinations, chelating ligands, anions, and two different organic compounds. The SCSC coordinating solvent exchange is thus demonstrated as a powerful method for the functionalization of MOFs.