Fluorescence‐based imaging in the second near infrared window (NIR‐II, 1000–1700 nm) is extensively used in both fundamental scientific research and clinical practice, owing to its advances of high sensitivity and high spatiotemporal resolution with increasing tissue penetration depths. Among several NIR‐II fluorophores, recent accomplishments in biocompatible lanthanide‐based luminescent nanomaterials have aroused great interest of researchers. This progress report summarizes recent progress in controlled synthesis of lanthanide‐based NIR‐II nanomaterials and their state‐of‐the‐art in NIR‐II biomedical imaging and biosensing applications. In addition, challenges and opportunities for this kind of novel NIR‐II nanoprobes are also discussed. This progress report provides an overview of lanthanide‐based nanomaterials for the state‐of‐the‐art biomedical imaging and biosensing applications in the second near‐infrared (NIR‐II) window. Typical mechanisms and synthetic strategies of these novel NIR‐II nanomaterials are summarized first, followed by deeply discussing the emerging challenges and opportunities for the future.