Metal–organic frameworks (MOFs) are hybrid porous materials with many potential applications, which intimately depend on the presence of chemical functionality either at the organic linkers and/or at the metal nodes. Functionality that cannot be introduced into MOFs directly via de novo syntheses can be accessed through post-synthesis modification (PSM) on the reactive moieties of the linkers and/or nodes without disrupting the metal–linker bonds. Even more intriguing methods that go beyond PSM are herein termed building block replacement (BBR) which encompasses (i) solvent-assisted linker exchange (SALE), (ii) non-bridging ligand replacement, and (iii) transmetalation. These one-step or tandem BBR processes involve exchanging key structural components of the MOF, which in turn should allow for the evolution of protoMOF structures (i.e., the utilization of a parent MOF as a template) to design MOFs composed of completely new components, presumably via single crystal to single crystal transformations. The influence of building block replacement on the stability and properties of MOFs will be discussed, and some insights into their mechanistic aspects are provided. Future perspectives providing a glimpse into how these techniques can lead to various unexplored areas of MOF chemistry are also presented.