The first women religious came to this country almost three centuries ago beginning what would become a journey of epic transformations, creating a powerful narrative of adaptation and survival, crossing a myriad of boundaries and barriers both physical and cultural. In some ways it is multiple narratives—reflecting and re-visioning changes across time and culture in the United States. In the long nineteenth century (through 1920), the sisters’ story is one of growth, risk taking, entrepreneurship, travel and adventure as well as one of poverty, suffering, bigotry, exploitation, and compromise. In the post-1920s era, their story became one of standardization, rigidity, massive institution-building, and diminishment as well as one of educational achievement, professionalism, social justice, modernization, gender awareness, and global outreach. Subsequently, by the early decades of the twenty-first century, sisters continue to adapt to the changing times, expanding their influence and presence within the larger national context and in the global milieu with fewer sisters, but a burgeoning global network. This analysis is not meant to be comprehensive in scope—it is impossible to discuss almost three centuries in one essay. However, I hope to discuss important milestones and themes that are embedded in the history and activities of American Catholic sisters in this expansive timeframe. My intent is to create, discuss, and analyze the larger context that defined and shaped the experience of Catholic sisters in the United States for almost three centuries. And, to provide nuance and analysis about their work, influence, and impact from their early institution-building in the nineteenth and early twentieth century to—most notably in the twentieth century—their focus and influence on social justice and transnationalism.