Signature detection is just a basic layer of protection. It is highly unreasonable to expect AV signature detection, HIPS, IDS, etc to catch everything.
Some type of virtualization or snapshot rollback ability is best option to deal with unknown\untrusted files.
Light virtualization is OK, but under rare circumstances it can be bypassed. Low enough incidence that it is nothing to fret about.
Snapshot is OK, but you have to uninstall for MBR modifiying updates and it too can be bypassed under rare circumstances - such as malicious firmware. Low enough incidence that it is nothing to fret about.
And I'm just talking about physical system protection here - without any consideration for network protection - which is an unwieldy beast to deal with all by itself.
Either way there is no bullet-proof solution or 100 % user friendly option. To believe otherwise or to think a completely bullet-proof config is possible is incorrect.
You can get to 98 - 99 %, but that last 5 to 10 % will require 90 % of your security config time and effort.
Pick what is reliable, easy for you to use, and that you like using - and it will all be OK.
If you do get infected (and I"m not talking about simple browser hijack that can be cleaned by using CCleaner), just clean install your OS and start from scratch... pretty simple concept.
The safe and secure bets remain the same - because they just work:
- AppGuard
- Sandboxie
- Shadow Defender
- ReHIPS
- Rollback Rx Home & Pro
- Drive Vaccine Rx
- Reboot Restore Rx
- Macrium Reflect