What attackers do. Attackers hide command and control traffic inside ordinary application protocols such as HTTP, HTTPS, DNS or mail protocols so it blends with legitimate traffic. This serves the Command and Control tactic.
How to defend. Route outbound traffic through controlled egress points such as proxies and DNS resolvers, and block direct internet access from servers that do not need it. Inspect traffic where policy allows, and use threat intelligence and domain reputation to flag known bad destinations. Collect proxy, DNS and firewall logs and correlate them with the process that made each connection.
Signs to look for. Watch for regular, beacon-like connections at fixed intervals, unusual user agents, rare or newly registered domains, and processes that do not normally talk to the internet doing so. The main gap is relying on port or protocol alone, since the traffic is designed to look normal.