It has been 55 years since the elucidation of the structure of DNA, suggesting an elegantly simple means for its self-replication. Who would have dreamed in 1953 that it would take longer for us to understand DNA replication than it would for us to uncover the basic rules of animal development? Without question, the mechanisms regulating where and when DNA replication initiates in the cells of our own body is the greatest remaining fundamental mystery in molecular biology. Cis-acting sequences that function as replication origins in mammalian cells have not been identified and the mechanisms that regulate where and when origins will fire during S-phase remain elusive. Indeed, the problem has been so difficult that most researchers move on to more lucrative fields. In this essay, I will summarize my laboratory's humble attempts to make some progress in this area. In doing so, I hope that I can inspire a few young scientists to breath fresh energy into this challenging field.