Breath-hold diving marine mammals are able to remain submerged for prolonged periods of time and dive to phenomenal depths while foraging. A number of physiological, biochemical and behavioral traits have been suggested that enable this life style, including the diving response, lung collapse, increased O2 stores, diving induced hypometabolism, and stroke-and-glide behavior to reduce dive metabolic cost. Since the initial studies by Scholander in the 1940‘s, when most of the physiological and biochemical traits were suggested, few have received as much study as the diving response and O2 management. The calculated aerobic dive limit (cADL) was an important concept which allowed calculation of the aerobic dive duration, and was defined as the total O2 stores divided by the rate of O2 consumption (metabolic rate). The total O2 stores have been defined for several species, and studies in both forced and freely diving animals have refined the metabolic cost of diving. Currently there appears to be little consensus about whether marine mammals perform a significant proportion of dives exceeding the cADL or not and there may be large differences between species. The diving response is a conserved physiological trait believed to arise from natural selection. The response includes diving-induced bradycardia, peripheral vasoconstriction, and altered blood flow distribution. While the response results in reduced cardiac work, it is not clear whether this is required to reduce the overall metabolic rate. An alternate hypothesis is that the primary role of the diving bradycardia is to regulate the degree of hypoxia in skeletal muscle so that blood and muscle O2 stores can be used more efficiently. Scholander suggested that the respiratory anatomy of marine mammals resulted in alveolar collapse at shallow depths (lung collapse), thereby limiting gas exchange. This trait would limit uptake of N2 and thereby reduce the risk of inert gas bubble formation and decompression sickness. In his initial treatise, Scholander suggested that alveolar collapse probably made inert gas bubble formation unlikely during a single dive, but that repeated dives could result in significant accumulation that could be risky. Despite this, lung collapse has been quoted as the main adaptation by which marine mammals reduce N2 levels and inert gas bubble formation. It was surprising, therefore, when recent necropsy reports from mass stranded whales indicated DCS like symptoms. More recent studies have shown that live marine mammals appear to experience bubbles under certain circumstances. These results raise some interesting questions. For example, are marine mammals ever at risk of DCS, and if so could N2 accumulation limit dive performance? While an impressive number of studies have provided a theoretical framework that explains the mechanistic basis of the diving response, and O2 management, many questions remain, some widely-accepted ideas actually lack sufficient experimental confirmation, and a variety of marine mammal species, potentially novel models for elucidating new diving adaptations, are understudied. The aim of this Frontiers Topic is to provide a synthesis of the current knowledge about the physiological responses of marine mammals that underlie their varied dive behavior. We also include novel contributions that challenge current ideas and that probe new hypotheses, utilize new experimental approaches, and explore new model species. We show that the field has recently entered a phase of renewed discovery that is not only unraveling more secrets of the natural diving response but will drive new applications to aid human exploration of the ocean depths. We also welcome comparative analyses, especially contributions that compare marine mammals with human divers.