Mucus is a complex hydrogel, comprising glycoproteins, lipids, salts, DNA, enzymes and cellular debris, covering many epithelial surfaces in the human body. Once secreted, mucin forms a barrier to protect the underlying tissues against the extracellular environment. Mucus can therefore adversely affect the absorption or action of drugs administered by the oral, pulmonary, vaginal, nasal or other routes. Solubility and lipophilicity are key factors determining drug absorption, as a drug has to be soluble in the body fluids at the site of absorption and must also possess enough lipophilicity to permeate the biological membrane. Evidence has accumulated over the past 40 years indicating that poorly soluble drugs will interact with mucus glycoprotein. Studies of the permeability of native or purified mucous gels are important when it comes to understanding the relative importance of hindered diffusion versus drug binding in mucous layers. This review highlights the current understanding of the drug-mucin interaction and also examines briefly the interaction of polymers and particles with the mucus matrix. While the concept of mucoadhesion was thought to provide an intensified and prolonged contact to mucosal absorption sites, mucopenetrating properties are nowadays being discussed for (nano)particulate carriers to overcome the mucus as a barrier and enhance drug delivery through mucus.