Modern angiosperm seeds, particularly orthodox seeds, can withstand dehydration to very low water contents. The concept of desiccation tolerance (DT) is interesting because it implies that an organism is capable of suspending growth and development as long as the water is available. The ability of seeds to survive in dry conditions allows them to form soil seed banks, travel further from their mother plants, and expand their habitat ranges as a result. Additionally, desiccation tolerance in seeds and dormancy determine whether seeds will germinate at the appropriate time to maximize seedling establishment, and therefore determine whether they will survive or be extinct. There is evidence that water potential is acquired in discrete stages during development that has different water activities and metabolic processes associated with them, which may be caused by specific desiccation stresses and discrete gene expression patterns. Thus, the attainment of different levels of desiccation tolerance may be determined by progressive acquisition of specific tolerance mechanisms or by sufficient accumulation of desiccation protectants. Desiccation-regulated genes, nonreducing sugar levels, and the efficiency of free radical-scavenging systems have all been identified as strategies to cope with cellular desiccation. Here, a review is made of the molecular mechanisms that enable cellular protection as well as their respective roles in desiccation tolerance. It is concluded that desiccation tolerance likely represents a multifactorial property with each component being equally important, rather than a single mechanism.