Research into lanthanide-doped organic–inorganic hybrid materials emerged in the 1990s with the development of interesting materials for optics: high efficiency and stable solid-state lasers, new fiber amplifiers and sensors, devices with upconversion, fast photochromic and non-linear responses, etc. Their interest relies on the possibility of combining properties of sol–gel host materials (shaping, tunable refractive index and mechanical properties, corrosion protection, specific adhesion, etc.) and the well-known luminescence of lanthanide ions (Ln). The fast development of photonic hybrids allowed the commercial exploitation of products with new or enhanced characteristics (megajoule pulsed Nd-YAG laser, protective coatings of glasses, screens or glasswares). However, recently, Ln-hybrid nanocomposites have found new applications in bio-sensors, bio-analytics and even clinical imaging diagnostics. These applications make use of the fluorescence properties of lanthanides that make luminescent hybrids ideal candidates for time-resolved fluoroimmunoassays, DNA hybridation assays, fluorescence imaging microscopy, or in vivo imaging. As a consequence, the goal of this review is twofold: (i) as a reminder of some general considerations that must be taken into account to design new optically active Ln-doped nanocomposites whatever the application field, and (ii) to show the most important advances achieved in the past years in different areas, paying special attention to bio-medical applications.