Human HIV infection remains incurable although several anti-HIV drugs have been identified and developed. Among these the nucleoside analogues were and remain in the forefront of anti-HIV chemotherapeutic regimens. Most of these nucleoside analogues are modified mainly in the sugar moiety. In general, they lack a free hydroxy group at the 3′-position. Consequently, they cannot participate in the formation of a 3′,5′-phosphodiester linkage, which renders the nucleoside 5′-triphosphates of such nucleoside analogues effective anti-HIV agents. Preventing the formation of 3′,5′-phosphodiester linkages leads to inhibition of the viral DNA strand elongation and ultimately chain termination. The phosphorylation of nucleoside analogues is a key factor in their efficacy as anti-HIV agents. Efficient phosphorylation depends largely on the structure of the nucleoside. Therefore, modification of the structure of nucleoside analogues are sought to enhance their phosphorylation and ultimately, effective inhibition of the HIV reverse transcriptase. This review is concerned with the trends in the design of nucleoside analogues as anti-HIV agents.