The introduction to this special issue argues that network breakdowns play an important and unacknowledged role in the shaping and emergence of scientific knowledge. It focuses on transnational scientific networks from the early modern Republic of Letters to 21st-century globalized science. It attempts to unite the disparate historiography of the early modern Republic of Letters, the literature on 20th-century globalization, and the scholarship on Actor-Network Theory. We can perceive two, seemingly contradictory, changes to scientific networks over the past four hundred years. At the level of individuals, networks have become increasing fragile, as developments in communication and transportation technologies, and the emergence of regimes of standardization and instrumentation, have made it easier both to create new constellations of people and materials, and to replace and rearrange them. But at the level of institutions, collaborations have become much more extensive and long-lived, with single projects routinely outlasting even the arc of a full scientific career. In the modern world, the strength of institutions and macro-networks often relies on ideological regimes of standardization and instrumentation that can flexibly replace elements and individuals at will.