Seasonal, pandemic and avian influenza viruses are able to infect humans, but the disease outcome often differs, ranging from mild upper respiratory tract disease to fatal pneumonia. The cell tropism of influenza viruses is thought to be an important determinant of these factors. Therefore, this review focuses on the factors that, together, determine the cell tropism of influenza viruses. These include: the receptor specificity of the viral hemagglutinin and the distribution of these receptors in the respiratory tract; the presence of inhibitory factors in the fluid lining the respiratory mucosa; and the requirement for host cell proteases that can cleave the precursor hemagglutinin of influenza viruses. Finally, we will discuss how the route of inoculation influences the cell types infected by influenza viruses and associated pathogenesis.