Centralization and Scalability issues I'd say.
+1
Centralization of mining. Our current network is easily at the mercy of a government 51% attack. It would take some global coordination, but it could probably be accomplished solely by seizing a handful of data centers. Of course bitcoin would be forked in such a scenario and the concept of cryptocurrencies in general would live on, so I don't think the governments have a reason to do such a thing. But if we accept that they could, then you have to ask yourself what is all the mining good for? A high difficulty provides an easy way to verify that blocks came from the one and only bitcoin network, so some proof of work is essential. But the cost of all the mining equipment is paid for by all bitcoin users and holders, so it is a reasonable question to ask ourselves how much hash power is enough? Over 3 million new coins will come on to the network over the next 3 years. At $1,000 per coin, that would be $3 billion of new value, so it would be reasonable to expect miners to spend, in aggregate, $3 billion to capture those coins.
Keeping in mind that with centralized mining, no amount of hash power will protect us from the government, is spending $3 billion necessary to protect the network from hackers? Maybe, $3b does not seem totally unreasonable. But lets say bitcoin goes to $5,000 per coin before this year is over. Then we are talking about a $15 billion investment in mining equipment. If our network's structure calls for an unnecessarily large investment in security, bitcoin would become vulnerable to a coin with a more economically efficient design.
Scalability. I actually see this as more of a political issue. The cost of transmitting, processing and storing bits will continue to fall as time goes on. That should mean the number of transactions the bitcoin network can process per minute should increase as well, at least for a given cost. Or put another way, the real costs per transaction should continually fall. Eventually, micro transactions should be able happen on-chain. Off-chain solutions will continue to exist, but those aren't really bitcoin offering a solution. The more powerful off-chain systems become, the less reliant on bitcoin they will be. As a bitcoin investor and holder, I want people to find use of bitcoin itself easy, cheap and irresistible. If off-chain solutions come to dominate usage of bitcoin, not only will btc become less valuable, but there is even a greater risk that those off-chain providers switch to some other chain entirely.
I say it's a political issue because of the blocksize limit.