Near-infrared (NIR) light is highly suitable for studying biological systems due to its minimal scattering and lack of background fluorescence excitation, resulting in high signal-to-noise ratios. By combining NIR light with lanthanide-based upconversion nanoparticles (UCNPs), upconversion is used to generate UV or visible light within tissue. This remarkable property has gained significant research interest over the past two decades. Synthesis methods are developed to produce particles of various sizes, shapes, and complex core-shell architectures and new strategies are explored to optimize particle properties for specific bioapplications. The diverse photophysics of lanthanide ions offers extensive possibilities to tailor spectral characteristics by incorporating different ions and manipulating their arrangement within the nanocrystal. However, several challenges remain before UCNPs can be widely applied. Understanding the behavior of particle surfaces when exposed to complex biological environments is crucial. In applications where deep tissue penetration is required, such as photodynamic therapy and optogenetics, UCNPs show great potential as nanolamps. These nanoparticles can combine diagnostics and therapeutics in a minimally invasive, efficient manner, making them ideal upconversion probes. This article provides an overview of recent UCNP design trends, highlights past research achievements, and outlines potential future directions to bring upconversion research to the next level. Near-infrared (NIR)-light is ideal for studying biological systems. Combined with lanthanide-based nanoparticles, UV or visible light is generated that can be utilized for diagnostic and therapeutic applications. Particle synthesis has advanced significantly, allowing for complex architectures. This article highlights recent achievements, remaining challenges in particle design and surface control, and the potential in biomedicine.image