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.