Nucleoside analogues have been the most successful antiviral compounds. Likewise, they are the most intriguing antiviral compounds, because of their structural relationship to natural nucleosides. This is also the reason why the design process of a potential selective antiviral nucleoside is so difficult. Too many natural processes (from cellular uptake to DNA incorporation) and too many enzymes are involved in their biological effect (activity/toxicity/catabolism/anabolism) to make the design process readily predictable. The relationship between the physicochemical and biochemical properties of nucleoside analogues and their antiviral activity is very complex and could only be understood on a very long term basis. Here we try to explain some of the reasoning that was made during the design process leading to new potent antivirals with a phosphonate functionality.