Seme was born at
Inanda, a small community of the American Zulu Mission of the
American Board of Commissioners for Foreign Missions. He was the last-born son of Isaka Seme and Eliza Bhulose, who were prominent mission members. He had ten siblings, including four brothers: Marsh, Nompondo, Mbekwana Isaac, and Lindley Ponqela. His six sisters were Lucy, Loti, Sannah, Speke, Dalitha, and Martha. The Seme family originated from the northern parts of what is today known as KwaZulu-Natal province in an area close to the
St Lucia estuary. His grandfather was Sinono, the son of Mbuyazi of Njonjo of Khuwana of Mqumbela of Sokoti of Seme. The Semes were members of the Mthethwas, one of the prominent polities in 18th and early 19th century southern Africa. The Bhuloses, Seme's mother people, are part of a much larger clan, which includes the Ndelus, the Mselekus, and the Dumas. Seme's family was influenced by the missionaries of the American Congregational Church, which is evident in the names of Seme's siblings. His eldest brother, Marsh, for instance, was named after Rev. Samuel Marsh, the founder of the American Zulu Mission at Thafamasi in Natal, while his brother Lindley was named after Rev.
Daniel Lindley, while Pixley himself took his name after Rev. Stephen Pixley. Similarly, his sisters, such as Dalitha, Lucy, Sannah, and Loti, were named after prominent female members of the American Zulu Mission. Until he arrived in Massachusetts in late 1898, Seme was known as Isaac. Only when he applied to study at Northfield Mount Hermon School did he change his name to Pixley, presumably in honor of Rev. Stephen Pixley, a missionary who had been instrumental in getting him to study in the United States of America. He changed his name again when he got to Columbia University in 1902 by adding 'ka Isaka' (son of Isaka). From then on, he became known as Pixley ka Isaka Seme. == Education ==