Provided are anti-CD73 antibodies or fragments thereof. The antibodies or fragments therefore include a VH CDR1 of SEQ ID NO: 1, a VH CDR2 of SEQ ID NO: 2, a VH CDR3 of SEQ ID NO: 3, a VL CDR1 of SEQ ID NO: 4, a VL CDR2 of SEQ ID NO: 5, and a VL CDR3 of SEQ ID NO: 6, or variants of each thereof. More generally, antibodies or fragments thereof are described which have specificity to one or more amino acid residues selected from the C-terminal half of a human CD73 protein, such as those in the C-terminal domains. Specific epitope amino acids in these domains include Y345, D399, E400, R401 and R480. Methods of using the antibodies or fragments thereof for treating and diagnosing diseases such as cancer are also provided.