It is generally accepted that the interaction of bacterial pathogenicity factors such as endotoxin (lipopolysaccharide, LPS) with molecules and cells of the human immune system, which eventually may lead to pathophysiological effects like septic shock, is exerted by isolated molecules after their release from the bacteria. Therefore, the study of the direct, physical interaction of LPS with target structures by applying biophysical means is of high interest. The questions which arise in this context concern the biologically active unit of LPS (monomer, multimer, aggregate), the molecular conformation of the single molecules, the type of aggregation of LPS polymers, the strength of their binding to serum and membrane proteins and/or unspecific binding to membrane phospholipids. Here, recent progress is reviewed which has increased our understanding of the processes preceding LPS-induced immune cell activation.