The discovery and investigation of metastable materials has only sparsely sampled the available design space. In this contribution, we explore a systematic approach to identifying metastable phases of interest in the vanadium-oxygen system. In particular, we report on the successful stabilization of several novel polymorphs and discuss their subsequent utilization as cathode materials in Li- and multivalent-ion batteries. A detailed elucidation of structure-function relationships that underpin their much-improved performance over the thermodynamically stable sink of the system, α-V2O5, has been performed based on structural characterization, elucidation of electronic structure, and first-principles calculations of diffusion pathways. The first example, ζ-V2O5, can be topochemically stabilized from the ternary quasi-1D β-MxV2O5 tunnel bronze and has been demonstrated to be far superior to its thermodynamically stable counterpart as a cathode material in both Li- and Mg-ion batteries. In particular, metastable ζ-V2O5 overcomes several challenges associated with α-V2O5, mitigating irreversible structural transitions and polaronic confinement effects that are a severe constraint on electrode applications of the thermodynamically stable phase. Mitigating these challenges allows for the unprecedented, fully reversible insertion of up to 3 Li+ per V2O5 as well as the highly reversible insertion of 0.33 Mg per V2O5 at moderately high operating voltages. In a second example, metastable γ’-V2O5 can be stabilized from the ternary γ-LiV2O5 phase and shows promising initial results as a cathode in both aqueous and non-aqueous Mg- and Ca-ion batteries. The role of metastability is central to explaining the improved performance of these metastable polymorphs and thereby insight gleaned from a fundamental evaluation of the origins of this behavior provides a glimpse into the importance of structure-function relationships and crystal structure motifs as they relate to metastability, further establishing the potential use of metastable materials as synthons for accessing underexplored compositional phase space.