Adenoviruses are the most commonly used viral vectors for clinical applications, mainly for the treatment of cancer and for the prevention of infectious diseases. A large number of adenoviruses—over 100 types have been isolated from humans—have evolved to infect different cells and tissues and to cause a range of diseases. As can be expected, several distinct entry mechanisms have been identified and characterized, which contribute to, or even determine cell and tissue tropism. Knowledge about adenovirus-host factors interactions is important for efficient and specific transduction of adenovirus vectors to cells and tissues of interest. Here we describe the state-of-the-art of human adenovirus cell entry, and discuss with perspectives outstanding questions in the field.