Lithium-ion batteries (LIBs) represent the most promising choice for meeting the ever-growing demand of society for various electric applications, such as electric transportation, portable electronics, and grid storage. Nickel-rich layered oxides have largely replaced LiCoO₂ in commercial batteries because of their low cost, high energy density, and good reliability. Traditional nickel-based oxide particles, usually called polycrystal materials, are composed of microsized primary particles. However, polycrystal particles tend to suffer from pulverization and severe side reactions along grain boundaries during cycling. These phenomena accelerate cell degradation. Single-crystal materials, which exhibit robust mechanical strength and a high surface area, have great potential to address the challenges that hinder their polycrystal counterparts. A comprehensive understanding of the growing body of research related to single-crystal materials is imperative to improve the performance of cathodes in LIBs. This review highlights origins, recent developments, challenges, and opportunities for single-crystal layered oxide cathodes. The synthesis science behind single-crystal materials and comparative studies between single-crystal and polycrystal materials are discussed in detail. Industrial techniques and facilities are also reviewed in combination with our group’s experiences in single-crystal research. Future development should focus on facile production with strong control of the particle size and distribution, structural defects, and impurities to fully reap the benefits of single-crystal materials.