Ribonucleotide reductase (RNR) is an enzyme essential to all forms of life, as it is responsible for catalyzing the first step in the production of the building blocks of DNA. Specifically, RNR actively facilitates the conversion of ribonucleoside diphosphates (NTP) to deoxyribonucleoside diphosphates (dNTPs). RNR regulation is essential for maintaining a balanced nucleotide pool. Tight control of the dNTP pool is essential for genomic stability, as nucleotide imbalances lead to severe effects on cell growth and survival. Thus, RNR is an attractive target for cancer and antiviral therapy. Recent work, from our group and others, have provided a molecular basis for understanding how RNR recognizes its diverse set of substrates and, particularly, how ATP and dATP behave as allosteric regulators of RNR. Additionally, our recent structural and biochemical/biophysical studies have been pivotal in describing how subunit oligomerization regulates RNR activity. Armed with an improved understanding of RNR function, we have been able to design and characterize chemotherapeutic agents that interact with RNR to regulate its functions.