The great majority of fusion reactor studies are based on the deuterium/tritium (D-T) fuel cycle through the reaction t(d,n)a. This reaction is chosen because it has the largest fusion cross-section (peaking at about 5 barns) and reaches this maximum cross-section at the lowest energy (~65 keV in the center-of-mass) of any potential fusion fuel. This large cross-section and low center-of-mass energy lead to the lowest confinement requirement for ignition (ignition in D-T requires a confinement triple-product nt_ET=4.9´10²¹ keV-s/m^-3 in the presence of a plausible impurity mix) and the highest fusion power density at fixed plasma pressure. The D-T fuel cycle also presents unique challenges to reactor designers. Two particular issues are the 14 MeV neutrons produced in the t(d,n)a reaction, and the presence of tritium in the fuel cycle. The 14 MeV neutrons damage reactor components (principally the structure of the blanket and shield) thereby limiting their useful lifetime; and activate materials, thereby opening the possibility that D-T fusion reactors will produce large volumes of radioactive wastes. Tritium does not occur in nature, but must be bred through the reaction n(⁶Li,t)a in a breeding blanket which surrounds the plasma. In situ breeding of tritium can result in large on-site tritium inventories (principally in the blanket and tritium recovery system) raising both safety and nuclear proliferation concerns.

Alternative ("advanced") fuel cycles have also been under investigation for many years. Two considerations have motivated these investigations are:

The three most common advanced fuel cycles are D-³He [which features the reaction ³He(d,p)a], "catalyzed DD" [that is, a primary cycle involving the two reactions d(d,n)³He and d(d,p)t together with the secondary reactions t(d,n)a and ³He(d,p)a to consume all t and ³He produced by the primary reactions], and p-¹¹B [which features the reaction ¹¹B(p,a)2a]

The D-³He fuel cycle has the advantage that it produces fewer neutrons than does the D-T fuel cycle. While the principle reaction ³He(d,p)a is aneutronic, neutron production via the side reaction d(d,n)³He and the secondary reaction d(t,n)a is unavoidable. The neutrons produced mainly have lower energy [2.45 MeV neutrons from d(d,n)³He reactions as opposed to 14 MeV neutrons from d(t,n)a reactions] so that material damage is reduced relative to the DT fuel cycle. Reactor studies show that the D-³He fuel cycle largely solves the reactor component lifetime issues associated with neutron damage, while neutron activation and the associated production of radioactive waste remains a concern. The D-³He fuel cycle avoids tritium, but does this by replacing it with another exotic isotope, ³He. ³He does not occur on earth in sufficient quantities to support a fusion power industry. However, ³He can be found on the moon, and proponents of the D-³He fuel cycle have suggested that it may be economic to mine ³He on the moon and transport it to earth to fuel a fusion power industry. The D-³He fuel cycle has a higher confinement requirement for ignition (ignition in D-³He requires a confinement triple-product nt_ET=2.4´10²³ keV-s/m^-3 in the presence of a plausible impurity mix), and a lower fusion power density at fixed plasma pressure.

The Catalyzed D-D fuel cycle avoids tritium without introducing any exotic isotopes, and thereby holds out the promise of an essentially unlimited supply of fuel for fusion power generation. The catalyzed D-D cycle actually produces more neutrons per unit of fusion power produced than the D-T cycle so that this fuel cycle does not address materials damage and activation concerns. The catalyzed D-D fuel cycle has a still higher confinement requirement for ignition (ignition in catalyzed D-D requires a confinement triple-product nt_ET=1.1´10²³ keV-s/m^-3 in the absence of impurities. Ignition in catalyzed DD cannot be achieved with a plausible impurity mix) and still lower fusion power density at fixed plasma pressure.

The p¹¹B fuel cycle avoids exotic isotopes, so that no breeding of fuel is required and the potential fuel supply is essentially unlimited. It is also nearly aneutronic, thus addressing materials damage and much of the materials activation concern. However, there are residual activation issues associated with high energy g-rays produced via the reaction ¹¹B(p,g)¹²C, and with neutron production from the reactions ¹¹B(a,n)¹⁴N and ¹¹B(p,n)¹¹C; and safety concerns associated with possible equilibrium inventories of MCi/GW of ¹¹C. More fundamentally, there is the problem that the p-¹¹B fusion reactivity is too low to compete with bremsstrahlung radiation losses, so that ignition (or even high fusion gain) cannot be achieved with this fuel.