Index: clang/include/clang/Basic/DiagnosticCommonKinds.td
===================================================================
--- clang/include/clang/Basic/DiagnosticCommonKinds.td
+++ clang/include/clang/Basic/DiagnosticCommonKinds.td
@@ -315,4 +315,9 @@
     "no analyzer checkers or packages are associated with '%0'">;
 def note_suggest_disabling_all_checkers : Note<
     "use -analyzer-disable-all-checks to disable all static analyzer checkers">;
+
+// Poison system directories.
+def warn_poison_system_directories : Warning <
+  "include location '%0' is unsafe for cross-compilation">,
+  InGroup<DiagGroup<"poison-system-directories">>, DefaultIgnore;
 }
Index: clang/lib/Frontend/InitHeaderSearch.cpp
===================================================================
--- clang/lib/Frontend/InitHeaderSearch.cpp
+++ clang/lib/Frontend/InitHeaderSearch.cpp
@@ -137,6 +137,13 @@
   SmallString<256> MappedPathStorage;
   StringRef MappedPathStr = Path.toStringRef(MappedPathStorage);
 
+  // If use system headers while cross-compiling, emit the warning.
+  if (HasSysroot && (MappedPathStr.startswith("/usr/include") ||
+                     MappedPathStr.startswith("/usr/local/include"))) {
+    Headers.getDiags().Report(diag::warn_poison_system_directories)
+        << MappedPathStr;
+  }
+
   // Compute the DirectoryLookup type.
   SrcMgr::CharacteristicKind Type;
   if (Group == Quoted || Group == Angled || Group == IndexHeaderMap) {
Index: clang/test/Frontend/warning-poison-system-directories.c
===================================================================
--- /dev/null
+++ clang/test/Frontend/warning-poison-system-directories.c
@@ -0,0 +1,27 @@
+// System directory and sysroot option causes warning.
+// RUN: %clang -Wpoison-system-directories -target x86_64 -I/usr/include --sysroot %S/Inputs/sysroot_x86_64_cross_linux_tree -c -o - %s 2> %t.1.stderr
+// RUN: FileCheck -check-prefix=WARN < %t.1.stderr %s
+// RUN: %clang -Wpoison-system-directories -target x86_64 -cxx-isystem/usr/include --sysroot %S/Inputs/sysroot_x86_64_cross_linux_tree -c -o - %s 2> %t.1.stderr
+// RUN: FileCheck -check-prefix=WARN < %t.1.stderr %s
+// RUN: %clang -Wpoison-system-directories -target x86_64 -iquote/usr/local/include --sysroot %S/Inputs/sysroot_x86_64_cross_linux_tree -c -o - %s 2> %t.1.stderr
+// RUN: FileCheck -check-prefix=WARN < %t.1.stderr %s
+// RUN: %clang -Wpoison-system-directories -target x86_64 -isystem/usr/local/include --sysroot %S/Inputs/sysroot_x86_64_cross_linux_tree -c -o - %s 2> %t.1.stderr
+// RUN: FileCheck -check-prefix=WARN < %t.1.stderr %s
+
+// Missing target but included sysroot still causes the warning.
+// RUN: %clang -Wpoison-system-directories -I/usr/include --sysroot %S/Inputs/sysroot_x86_64_cross_linux_tree -c -o - %s 2> %t.2.stderr
+// RUN: FileCheck -check-prefix=WARN < %t.2.stderr %s
+
+// With -Werror the warning causes the failure.
+// RUN: not %clang -Werror=poison-system-directories -target x86_64 -I/usr/include --sysroot %S/Inputs/sysroot_x86_64_cross_linux_tree -c -o - %s 2> %t.3.stderr
+// RUN: FileCheck -check-prefix=ERROR < %t.3.stderr %s
+
+// Cros target without sysroot causes no warning.
+// RUN: %clang -Wpoison-system-directories -Werror -target x86_64 -I/usr/include -c -o - %s
+
+// By default the warning is off.
+// RUN: %clang -Werror -target x86_64 -I/usr/include --sysroot %S/Inputs/sysroot_x86_64_cross_linux_tree -c -o - %s
+
+// WARN: warning: include location {{[^ ]+}} is unsafe for cross-compilation [-Wpoison-system-directories]
+
+// ERROR: error: include location {{[^ ]+}} is unsafe for cross-compilation [-Werror,-Wpoison-system-directories]