diff --git a/ci/azure-linux_mac.yml b/ci/azure-linux_mac.yml
index 6a5c24b78..cafab64aa 100755
--- a/ci/azure-linux_mac.yml
+++ b/ci/azure-linux_mac.yml
@@ -32,7 +32,7 @@ steps:
         sudo make install
         popd
     else
-        brew install bcftools
+        brew install bcftools automake
     fi
 
     # Install autoconf/automake (required for htslib)
diff --git a/ci/native_libs-linux_osx.yml b/ci/native_libs-linux_osx.yml
index e49421738..da12d5548 100755
--- a/ci/native_libs-linux_osx.yml
+++ b/ci/native_libs-linux_osx.yml
@@ -13,7 +13,7 @@ steps:
             sudo make install
             popd
         else
-            brew install bcftools
+            brew install bcftools automake
         fi
 
         # Install autoconf/automake (required for htslib)
diff --git a/docker/Dockerfile-cli b/docker/Dockerfile-cli
index 3cb02cd55..bc9a2347c 100644
--- a/docker/Dockerfile-cli
+++ b/docker/Dockerfile-cli
@@ -5,7 +5,7 @@ ENV AWS_EC2_METADATA_DISABLED true
 # Install some dependencies
 RUN yum -y install cmake3 which wget git tar gzip unzip gcc-c++ zlib-devel \
        openssl-devel bzip2-devel libcurl-devel xz-devel make \
-       automake autoconf \
+       automake autoconf patch \
     && yum clean all
 
 WORKDIR /tmp
diff --git a/libtiledbvcf/cmake/Modules/FindHTSlib_EP.cmake b/libtiledbvcf/cmake/Modules/FindHTSlib_EP.cmake
index 629279cb2..0c86eeb69 100644
--- a/libtiledbvcf/cmake/Modules/FindHTSlib_EP.cmake
+++ b/libtiledbvcf/cmake/Modules/FindHTSlib_EP.cmake
@@ -60,6 +60,7 @@ FIND_PACKAGE_HANDLE_STANDARD_ARGS(HTSlib
   REQUIRED_VARS HTSLIB_LIBRARIES HTSLIB_INCLUDE_DIR
 )
 
+
 if (NOT HTSLIB_FOUND)
   if (SUPERBUILD)
     message(STATUS "Adding HTSlib as an external project")
@@ -74,6 +75,12 @@ if (NOT HTSLIB_FOUND)
     if (BUILD_TYPE STREQUAL "DEBUG")
       SET(CFLAGS "-g")
     endif()
+
+    # required to updated htslib configure.ac with autoconf 2.70
+    #   - see https://github.com/samtools/htslib/commit/680c0b8ef0ff133d3b572abc80fe66fc2ea965f0
+    #   - and https://github.com/samtools/htslib/pull/1198/commits/6821fc8ed88706e9282b561e74dfa45dac4d74c8
+    find_program(AUTORECONF NAMES autoreconf REQUIRED)
+
     ExternalProject_Add(ep_htslib
       PREFIX "externals"
       URL "https://github.com/samtools/htslib/archive/1.10.zip"
@@ -82,13 +89,15 @@ if (NOT HTSLIB_FOUND)
       CONFIGURE_COMMAND
           autoheader
         COMMAND
-          autoconf
+          ${AUTORECONF} -i
         COMMAND
           ./configure --prefix=${EP_INSTALL_PREFIX} LDFLAGS=${EXTRA_LDFLAGS} CFLAGS=${CFLAGS}
       BUILD_COMMAND
         $(MAKE)
       INSTALL_COMMAND
         $(MAKE) install
+      PATCH_COMMAND
+        patch -N -p1 < ${CMAKE_CURRENT_SOURCE_DIR}/cmake/patches/htslib-1.10-config.patch
       BUILD_IN_SOURCE TRUE
       LOG_DOWNLOAD TRUE
       LOG_CONFIGURE TRUE
@@ -114,4 +123,4 @@ endif()
 if (EP_HTSLIB_BUILT AND TARGET HTSlib::HTSlib)
   include(TileDBCommon)
   install_target_libs(HTSlib::HTSlib)
-endif()
\ No newline at end of file
+endif()
diff --git a/libtiledbvcf/cmake/patches/htslib-1.10-config.patch b/libtiledbvcf/cmake/patches/htslib-1.10-config.patch
new file mode 100644
index 000000000..2c6e7443d
--- /dev/null
+++ b/libtiledbvcf/cmake/patches/htslib-1.10-config.patch
@@ -0,0 +1,31 @@
+From 6821fc8ed88706e9282b561e74dfa45dac4d74c8 Mon Sep 17 00:00:00 2001
+From: John Marshall <jmarshall@hey.com>
+Date: Fri, 1 Jan 2021 10:37:22 +0000
+Subject: [PATCH] Don't set $host_alias as that confuses autoconf 2.70
+
+Autoconf 2.70 is more careful about cross compilation, so with this
+version using AC_FUNC_MMAP implies AC_CANONICAL_HOST and hence computes
+$build/build_alias/host/host_alias/etc. Setting $host_alias ourselves
+interferes with that. Hat tip Matthias Klose (via debbug#978835).
+
+As autoconf 2.70 implicitly uses AC_CANONICAL_HOST, it requires (and its
+autoreconf --install installs) config.guess and config.sub. Ignore those,
+and ignore install-sh as well for good measure.
+---
+diff --git a/configure.ac b/configure.ac
+index 9bd1642d7..f473c97e5 100644
+--- a/configure.ac
++++ b/configure.ac
+@@ -137,9 +137,9 @@ AC_ARG_ENABLE([s3],
+                   [support Amazon AWS S3 URLs])],
+   [], [enable_s3=check])
+ 
+-test -n "$host_alias" || host_alias=unknown-`uname -s`
+-AC_MSG_CHECKING([shared library type for $host_alias])
+-case $host_alias in
++basic_host=${host_alias:-unknown-`uname -s`}
++AC_MSG_CHECKING([shared library type for $basic_host])
++case $basic_host in
+   *-cygwin* | *-CYGWIN*)
+     host_result="Cygwin DLL"
+     PLATFORM=CYGWIN