Metal-organic frameworks (MOFs) are modular porous materials synthesized from metal cluster nodes and organic linkers that connect these nodes. This rapidly expanding class of structures presents viable platforms for applications in gas sorption and separation, catalysis, sensing, fuel processing, and environmental remediation and as porous conductive materials. These applications are increasingly relying on sophisticated ligands that have functional characteristics either as independent entities (that is, outside of MOFs) or that gain new functions once reticulated into the porous material. Thus, the traditionally inorganic area of MOF research begins to profit more and more from a comprehensive approach which combines insights from organic, inorganic, and materials chemistry. This Perspective highlights some of the second-generation MOFs prepared and studied using this holistic approach.