Monacolin-K is a strong anti-hypercholesterolemic agent produced by Monascus ruber via polyketide pathway. In this study, we intended to develop monacolin-K high-yielding mutants through rational screening strategies based on the understanding of monacolin-K biosynthetic pathway. NTG-treated mutants, especially showing resistance to antimetabolites(2-chloroacetamide and 2-deoxyglucose) and/or  an polyene antibiotic(nystatin) demonstrated remarkably higher production of monacolin-K than the corresponding mother strains, proving that the rational screening strategies were very efficient in the selection of high yielding producers. Notably, it was found that when the screened mutants were cultivated in shake flask cultures, almost all the high-yielding mutants showed compact-pelleted morphology(the diameter of the pellets ranging below 1mm), whereas relatively low-producing mutants showed thick and viscous mycelial forms. Therefore, it was concluded that both the intrinsic producers' capability of monacolin-K biosynthesis and the good morphological characteristics of the high-yielding mutants should lead to the higher production of monacolin-K.