diff --git a/Library/Homebrew/exceptions.rb b/Library/Homebrew/exceptions.rb
index 142688cfd0..f7a442eb08 100644
--- a/Library/Homebrew/exceptions.rb
+++ b/Library/Homebrew/exceptions.rb
@@ -320,6 +320,18 @@ class FormulaConflictError < RuntimeError
   end
 end
 
+class FormulaUnknownPythonError < RuntimeError
+  def initialize(formula)
+    super <<~EOS
+      The version of Python to use with the virtualenv in the `#{formula.full_name}` formula
+      cannot be guessed automatically because a recognised Python dependency could not be found.
+
+      If you are using a non-standard Python depedency, please add `:using => "python@x.y"` to
+      `virtualenv_install_with_resources` to resolve the issue manually.
+    EOS
+  end
+end
+
 class FormulaAmbiguousPythonError < RuntimeError
   def initialize(formula)
     super <<~EOS
diff --git a/Library/Homebrew/language/python.rb b/Library/Homebrew/language/python.rb
index 75d79a6f8d..c3538f0ddf 100644
--- a/Library/Homebrew/language/python.rb
+++ b/Library/Homebrew/language/python.rb
@@ -182,6 +182,7 @@ module Language
         if python.nil?
           pythons = %w[python python3 python@3 python@3.7 python@3.8 pypy pypy3]
           wanted = pythons.select { |py| needs_python?(py) }
+          raise FormulaUnknownPythonError, self if wanted.empty?
           raise FormulaAmbiguousPythonError, self if wanted.size > 1
 
           python = wanted.first