Provided herein are methods of detecting circulating tumor DNA, cancer cell mutations, and/or cancer cells harboring one or more cancer cell mutations. In some embodiments, methods provided herein include detecting one or more genetic alterations in cell-free DNA. In some embodiments, methods provided herein for detecting one or more genetic alterations in cell-free DNA can be performed when the subject is not known to harbor a cancer cell and/or a cancer cell mutation (e.g., when the subject is not known to harbor a cancer cell having the cancer cell mutation).