Humans are members of a completely terrestrial species; thus, they are biologically adapted to a lifestyle incompatible with the pelagic environment. This notwithstanding, humans have evolved cultural adaptations to all kinds of environmental conditions, and technology allows them to temporarily stay in hostile environments. Such interactions are necessary to move from one site to another (travel), or to extract resources (food) necessary to survive. The interaction with the open ocean can be, in addition, involuntary or indirect when the by-products of human activities (oil, litter) arrive at the open sea. On the other hand, we can distinguish small-scale interactions from large-scale interactions. Small-scale interactions have a disturbance effect on the open sea biota, which is only local and/or spatially limited in comparison with the whole pelagos. These are the cases of echo-sound production (by a limited number of ships, and for only limited purposes), mineral extraction (limited at a close number of sites where a building is necessary to carry out the extraction), or ship navigation routes (frequently crossed by ships of any size but, in any case, at the surface of the ocean). Such interactions heavily impact the pelagic environment in a very limited area (if compared with the pelagos dimension), and although the total pelagos can be considered not impacted locally, they produce alterations, disturbances, and/or variations in the community’s composition (in coastal areas, more than elsewhere). Large-scale interactions are human activities that have existed for a long time, with an intense geographic distribution, in deeper areas of the pelagos. Among such interactions, we can consider fishery activity (an intentional one) and all indirect interactions (such as litter production and alteration of the gas composition of the atmosphere). A final interaction of humans with the open ocean is, hopefully, going to affirm on a large scale, the study (small scale, direct) and management with conservative purposes.