Peggy O'Rourke, forced with her family to leave Ireland during the Potato Famine, is the only one to survive the treacherous Atlantic crossing on the infamous coffin ships to America. She journeys from the great city port to the village of Sing Sing, New York where she starts to build her own future.

James, one of Peggy's two sons, grows up to become a keeper at the notorious Sing Sing Prison. His actions there bring disgrace upon the family and set in motion the mysterious disappearance of his 5-year-old daughter. In his grief, James rules his family like a prison guard, burdening the life of his eldest son, who spends his adulthood searching for his lost sister.

Lost on Cherry Street follows three generations in their search to build a new life of prosperity in America against the greatest tragedy any family can face. Will the truth bring answers of comfort or pain?