From the perspectives of evolutionary history and drug resistance, the classification and characterization of cytochrome P450 monooxygynases in Aspergillus species have shown numerous structure-function correlates of the enzyme and its variations. Aspergillus is one of the major pathogens of the respiratory tract that deteriorate the prognosis of various pulmonary diseases. The prognosis of the target diseases is further impacted due to the emergence of azole resistance. This article explores the attributes of azole resistance of Aspergillus strains with regard to point mutations and polymorphisms in CYP51 and CYP51 from an in-silico perspective. Studies reveal that Aspergillus requires CYP51A and CYP51B for full functionality. The CYP51 in Aspergillus is chemically 14-alpha demethylase which converts lanosterol to ergosterol. Ergosterol helps in the membrane fluidity and virulence of the fungal isolate. The enzyme is also the target of azoles, especially the active heme molecule within the active site. The current study shows that deletion mutations in CYP51 could lead to over expression of 14-alpha demethylase which could be considered a novel mechanism for azole resistance. Moreover, the deletion mutations could also potentiate the over activity of the ABC transporter proteins (efflux pump) because the alignment of the amino acid residues in mutated CYP51 nearly matched that of ABC transporter proteins in the same fungal isolate. It was further contended that deletion mutations in CYP51 promoter could prevent the inhibitory effects of transcription factors on CYP51 expression which could be considered as another method for azole resistance.