Sex determination and differentiation are basic events of development and key processes of sexual reproduction. The mechanism of sex determination and differentiation is both baffling and intriguing. Mollusca is the second largest animal phylum, harboring diverse sexual systems including hermaphroditism, gonochorism, protandry and sex reversal. Therefore, molluscs are an ideal animal group to study the mechanisms of sex determination and differentiation. Although efforts towards understanding sex determination and differentiation of molluscs can be traced back to the 1940s, the mechanisms of sex determination and differentiation of molluscs remain enigmatic. Solving the riddle of sex determination and differentiation and identifying key genes would help us better understand the biology of molluscs and provide insights into sexual evolution in the animal kingdom. Here we review the research progress and the prospects of sex determination and sex related genes such as Dmrt, Foxl2, Sox, Wnt4, Dax1, β-catenin, Fem-1, Vasa, Nanos and GnRH in molluscs. We also propose several goals about mechanistic underpinning of sex determination in molluscs which require further study.