Cell cycle checkpoints are stress response mechanisms that are commonly defective in cancers, including melanoma. These defects can be selectively targeted to deliver lethal insult to the melanomas, normal tissue being protected by their functional checkpoints. We have investigated a number of checkpoint responses that are defective in melanomas that are likely to contribute to the genomic instability and endogenous stress characteristic of this cancer. These defects have been targeted using either a candidate or unbiased synthetic lethal approaches. We have also attempted to identify molecular markers of the checkpoint defects that will have potential clinical utility to identify patients most likely to benefit form these targeted therapies.