During the early stage of the adenovirus infection, the virion binds to a "primary receptor" on the host cell plasma membrane via the fibre projection jetting out of the penton base capsomers located at the twelve apices of the icosahedral capsid. The second step consists of a receptor-mediated endocytosis which involves membrane integrin molecules (the "secondary receptors") and the RGD and/or LDV motifs of penton base. The latter step is inhibited at low temperature, whereas virus attachment to its primary receptor is temperature-independent. Two different primary receptors with a high affinity for the Adenovirus have been recently identified. One is common to Coxsackievirus B3 and adenovirus (CAR), the other one corresponds to a conserved region of the alpha-2 domain of the heavy chain of the major histocompatibility complex class I molecules (MHC-I-alpha 2), overlapping tryptophane-167. The receptor usage by the virus is governed by both cellular and viral parameters. On the cellular side, the relative abundance of one versus the other type of primary receptors would theoretically determine the virus choice: CAR receptor has been mainly found in tissues from mesodermic origin, whereas MHC-I-alpha 2 is ubiquitous. On the virus side, the molecular determinants of the receptor usage have been mapped to the terminal knob of the fiber projection, and have been found to be different for CAR and MHC-I-alpha 2. CAR recognizes linear motifs in fiber knobs in a subgroup-dependent manner, as it binds to all Adenovirus serotypes except for the subgroup B members. MHC-I-alpha 2 however recognizes conformational epitopes carried by fiber knobs from all serotypes tested including subgroup B members. These results should have significant implications in the cell targeting of adenoviral vectors used in gene therapy.