Major structural changes:
- "Flip the chain", instead of committing to new transactions, commit to the summaries of open transactions:  
- Increased efficiency for merged mining, restructure the primary header to make the bitcoin specific data non-mandatory. (e.g. the block chain specific stuff would go into second header connected by a header tree), making the primary headers pure timestamps.
Transaction behavior changes:
- Improved signature types to allow for partial malleability of outputs. (e.g. make it easier to add a fee onto someone elses transaction, or to take fees from a transaction without outputs set aside for that putpose)
- Pervasive ECC public key-recovery to reduce transaction sizes (can be done partially without breaking compatibility completely)
- Support for a post-quantum signature scheme. Lamport signatures have nice intuitive security properties, but it and all other similar schemes have extreme space requirements that would require structural changes to the blockchain to accommodate.
Navel gazing / Protocol housekeeping:
- Byte order consistency
- Eliminate redundancies in the variable length integer encodings
- Avoiding hashes covering malleable fields
- CHECKMULTISIG popping one-too-many items off the stack
- difficulty adjustment periods should overlap (prevent potential 'timejacking')