Metal-organic frameworks (MOFs) are a class of hybrid inorganic-organic crystalline porous materials composed of inorganic cluster and organic linker building units. MOFs can combine the advantages of material properties and molecular design into a single multifunctional platform. With functional capabilities possible at each discrete building unit and in the framework architecture as a whole, the tunability of the MOF platform has emerged as an attractive property that can be harnessed to design novel nanomedicines. This dissertation focuses on the exploration of molecular design to enhance the anticancer efficacy of various multifunctional nanoscale MOFs (nMOFs) in combination with localized cancer therapeutic modalities, including photodynamic therapy (PDT), sonodynamic therapy (SDT), and radiotherapy (RT). Chapter 1 of this thesis introduces the general concept, history, advantages, and research directions of nMOFs. The synthetic strategies and postsynthetic molecular functionalization approaches are also discussed. Additionally, to put nMOFs’ utility in nanomedicine into context, the advantages and disadvantages of various local cancer therapeutic modalities are weighed. Chapter 2 describes the PDT enhancement of surface-anchored zinc-phthalocyanine (ZnOPPc) photosensitizers (PSs) on a 2D Hf12-based MOF, also known as a metal-organic layer (MOL). Typically, PSs are loaded into a 3D MOF as the bridging linkers, but in this chapter we find that surface-anchoring the PS to the secondary building units (SBUs) of a MOL changes its local environment and makes it more accessible to ground state oxygen (3O2) for enhanced production of cytotoxic singlet oxygen (1O2). The ZnOPPc@MOL assembly demonstrates highly effective anticancer efficacy in vitro and in vivo on mouse models. Chapter 3 presents another PDT design strategy by loading the ZnOPPc PSs into MOF pores. The MOF pores act as cages to isolate hydrophobic ZnOPPc PSs and prevent their aggregation-induced quenching. Non-covalent trapping of ZnOPPc PSs does not adversely affect the photophysical properties of ZnOPPc. As a result, ZnOPPc@MOF significantly enhances the 1O2 generation efficiency compared to previous MOFs, thus allowing the highly potent ZnOPPc PSs to reach their full potential in PDT. ZnOPPc@MOF exhibited extremely effective in vitro and in vivo anticancer efficacy, with >99% tumor growth inhibition and 80% cure rates on two murine colon cancer models. Chapter 4 describes the synthesis of the first 3D Zr- and Hf-nMOFs with Pc-based bridging ligands. Due to the synthetic challenges, poor solubility, and inflexible/incompatible symmetry of phthalocyanines, Pc-based MOFs have been extremely elusive to the MOF community, with no 3D Pc-based MOFs reported to date. In this chapter we report the first example of using an N-alkylated tetraimidazophthalocyanine to grow 3D nMOFs with Zr or Hf SBUs and a cubic PCN-221 structure. Chapter 5 demonstrates the SDT performance of surface-anchored sensitizers on a Hf12 SBU- and iridium PS linker-based nMOL platform and investigates its mechanism of 1O2 generation. The TBP@MOL (TBP = 5,10,15,20-tetra(p-benzoato)porphyrin) assembly efficiently captures broad-spectrum sonoluminescence through both the Ir-PS linker and anchored porphyrin sensitizers, where the excited Ir-PS linkers (donors) can then transfer energy directly to the porphyrin units (acceptors). The energy transfer synergizes with the highly flexible and accessible sensitizers to significantly enhance 1O2 generation and in vivo SDT anticancer efficacy.