Disease. It's the one thing over which humanity has very little control. Did you read that right? Yes, you did. Germs may not know we exist, but they are out to get us, and it is quite possible that they will. There is no hope of conquering disease, only a series of lucky, temporary defenses.
The first, interesting thing about diseases is that they adapt and evolve to their environments, for instance you. As you mount defenses against them, in the form of drugs or developing natural resistance, the diseases find new and interesting footholds. There is no cure for the common cold, only ways to alleviate its symptoms. There are several different strains of HIV already.
Humans have a way of helping diseases along, especially now in this overpopulated world. HIV is believed to have arisen from careless handling of bushmeat. The meat of the primate which is believed to have infected 'Patient Zero', the first person to carry and transmit the disease was a function of poverty. As humans found greater exposure to nature, so they came into contact with the disease. It's the same story with many diseases: the Hanta Virus, Legionnaire's disease, Ebola and others. There are new and interesting diseases waiting to be discovered.
Then there are trajectories to contend with. Humans need proximity to other humans to transmit diseases. The global population is growing too rapidly to believe that a fertile disease trajectory can be avoided. People come into contact with other people, no matter what can be done. People travel now.
Socio-economic conditions also contribute to the problem. There was poverty in the past, and their were unhygienic conditions, but as poverty increases, so do conditions that foster disease: a lack of clean water and poor sanitation to name two of the most difficult conditions.
Human behaviour fosters compromised immune systems. Aside from unclean conditions and risky sexual behaviour, too much cleanliness does not allow for the immune system to develop. On the other hand, overuse of medications has forced germs to evolve more rapidy leading to drug-resistant strains.
Finally, what if two diseases exchanged genetic material? What if, for instance, HIV crossed with the common cold, leading to something airborne which mutated extremely rapidly.
The disease dystopia
As the population grows, humans will have less and less defense against rapidly evolving diseases and new diseases. A catastrophic outbreak of something is expected, but as germs and bacteria approach chaotic variability, science has difficulty planning ahead, and outbreaks have to be dealt with on a reactive basis. The zombie apocalypse, or at least something equally devastating and deadly, is not so far-fetched after all.