This lecture is about how clinical microbiologist and infectious disease specialist discover and characterize new microbial agents causing outbreaks of infectious diseases. The discovery of novel microbe in the outbreak setting depends on our ability to differentiate whether this one particular epidemic is different from other usual outbreaks which are usually happening on a seasonal basis. The first suspicion is often raised by frontline doctors who notice an unusual increase in the number of cases, change in the pattern of symptomatology, disease severity and unexpected investigative findings in patients under their care. The clinical laboratory consultants may also raise their first suspicion by finding something that grows in their culture test that cannot be identified by their conventional testing panel. But sometimes this is the veterinarians or farmers who first noticed an unusual pattern of animal deaths followed by a human death with history of exposure to the affected animals. And especially in countries with either a suboptimal health infrastructure or information transparency, rumors of new disease outbreaks are often spread by word of mouth which then appear on the web and the foreign news media. In this newspaper cutting in February 2003, there is a report of an outbreak of pneumonia which affected 305 people in six cities of Guangdong in China. There were rumors that the disease was rapidly spreading. These rumors were condemned by officials, but the cause of the outbreak was uncertain and clinical samples were sent to the nation's capital city laboratory for further testing. There were even rumors that this may be a bioterrorist attack with agents causing anthrax and plague. This was excluded by the officials and the cause was attributed to influenza. What is most discomforting is that 105 out of the first 305 cases of pneumonia are medical staff such as doctors and nurses who looked after these patients. While this outbreak was still in Guangdong, our department of microbiology in Hong Kong was already very alarmed and wanted to find out what is the root cause of this possible emerging infectious disease outbreak. Because it was reported that there was an increasing incidence of atypical pneumonia of unknown cause and this was in our geographical proximity. About one third of these patients are health care workers with some deaths. Moreover the disease was spreading from city to city and might finally cross the border to Hong Kong. And there were informal reports that the initial cases were related in time, place and occupation. Some of the initial cases were restaurant chef, hospital workers and family members. Just 12 days after the news report, we were consulted to see a patient at Kwong Wah Hospital in Hong Kong. He was a 64 year old doctor working in Guangzhou who traveled to Hong Kong. He has contacted patients with atypical pneumonia two weeks ago in Guangzhou. He then developed fever, chills, running nose, dry cough, muscle pain, headache and left chest pain on inspiration. A few days later, he treated himself with antibiotics active against typical and atypical bacteria which can cause pneumonia. But his fever soon recurred after a short period of subjective improvement. At the time of admission, he was running a fever with tachycardia (a fast pulse rate), his blood oxygen saturation was down to only 65 percent, and he was therefore breathing very rapidly at 26 times per minute. There were diffuse fine crepitations on auscultation of his chest. Investigation showed that he had decreased lymphocyte count down to only 0.6. His liver enzymes were elevated which indicated liver impairment. His chest X-ray showed bilateral diffuse fine ground glass changes which is classical of interstitial pneumonia.