Method to detect resistance of a microorganism to a specific antimicrobial drug, said method comprising the steps of: (a) digesting a sample comprising proteins of a microorganism with an endoprotease, wherein said sample is a crude cell lysate or a patient specimen, wherein said sample contains or is suspected of containing a drug resistance conferring protein, wherein said endoprotease cleaves at a specific site of the protein resulting in a mix of peptides representing a protein digest, wherein different amino acid substitutions in the sequence of the protein result in different peptides upon digestion and wherein each protein renders specific peptides upon digestion such that when the cleavage action of the protease and the amino acid sequence of a protein are known, the cleavage profile of different peptides in the protein digest including the mass of the different peptides may be predicted; (b) acquiring a mass spectrum of the mix of peptides obtained in step (a) by high resolution mass spectrometry at a resolution of 1-10 ppm, wherein said mass spectrum provides information on whether said drug resistance conferring protein is present, on the type of drug resistance conferring protein and on amino acid substitutions in the sequence of the drug resistance conferring protein to thereby allow for the precise assessment of peptides and identification of the specific drug resistance conferring protein and/or amino acid substitution mutations therein; (c) identifying from the mass spectrum under (b) a resistance conferring protein by identifying an amino acid substitution mutation in said resistance conferring protein, using reference peptides from resistance conferring proteins wherein said reference peptides include an amino acid substitution mutation that confers resistance, to thereby determine the resistance of the microorganism. (a) digesting a sample comprising proteins of a microorganism with an endoprotease, wherein said sample is a crude cell lysate or a patient specimen, wherein said sample contains or is suspected of containing a drug resistance conferring protein, wherein said endoprotease cleaves at a specific site of the protein resulting in a mix of peptides representing a protein digest, wherein different amino acid substitutions in the sequence of the protein result in different peptides upon digestion and wherein each protein renders specific peptides upon digestion such that when the cleavage action of the protease and the amino acid sequence of a protein are known, the cleavage profile of different peptides in the protein digest including the mass of the different peptides may be predicted; (b) acquiring a mass spectrum of the mix of peptides obtained in step (a) by high resolution mass spectrometry at a resolution of 1-10 ppm, wherein said mass spectrum provides information on whether said drug resistance conferring protein is present, on the type of drug resistance conferring protein and on amino acid substitutions in the sequence of the drug resistance conferring protein to thereby allow for the precise assessment of peptides and identification of the specific drug resistance conferring protein and/or amino acid substitution mutations therein; (c) identifying from the mass spectrum under (b) a resistance conferring protein by identifying an amino acid substitution mutation in said resistance conferring protein, using reference peptides from resistance conferring proteins wherein said reference peptides include an amino acid substitution mutation that confers resistance, to thereby determine the resistance of the microorganism.