Handbrake is (mostly) a GUI for x264, which is the best H.264 encoder out there.
Depending on what display you are using (size, resolution, and type) then re-encoding may produce acceptable results.
I find that a 50GB disc usually has 25-30GB reserved for the main feature (sometimes less) and many people seem happy with the quality achieved by compressing that to about 10-15GB via Handbrake.
Personally, I do notice this loss of quality - especially if you will be upscaling it (e.g. on a 4K display) and the process is far too time consuming/CPU intensive for it to be worthwhile in my opinion.
Play around with the CRF settings until you find something which produces acceptable results.
Turning up the encoder settings from the defaults can improve quality for any given size, but greatly increase encoding time.
Any time I tried this though, I ended up turning the encoder settings up as high as they went, and after settling on a CRF setting which looked good, the file size was almost the same if not larger than the original.
These days I will either rip to ISO if I don't have any time to spend looking over a disc, or use MakeMKV to extract the main title.
Usually I end up converting to MKV fairly shortly after - most discs only take a minute or so of playback/seeking to determine whether they will be easy or "complex" to rip.
E.g. lots of different titles to sort through, finding whether they contain non-English dialog/subs etc.
I use this as a preset (save it as a .mmcp.xml file in the MakeMKV directory) which greatly simplifies things - though it does still require some intervention.
<?xml version="1.0" encoding="utf-8"?>
<profile>
<!-- profile name - Default -->
<name lang="eng">Custom</name>
<!-- Common MKV flags -->
<mkvSettings
ignoreForcedSubtitlesFlag="true"
useISO639Type2T="false"
setFirstAudioTrackAsDefault="true"
setFirstSubtitleTrackAsDefault="true"
setFirstForcedSubtitleTrackAsDefault="true"
insertFirstChapter00IfMissing="true"
/>
<!-- Settings overridable in preferences -->
<profileSettings
app_DefaultSelectionString="-sel:all,+sel:(eng|favlang|nolang),-sel:(havemulti|havelossless|core|forced|lossy*(!eng)), -sel:subtitle*(!eng), -sel:mvcvideo,-sel:special, =100:all,-10:favlang"
/>
<!-- Output formats currently supported by MakeMKV -->
<outputSettings name="copy" outputFormat="directCopy">
<description lang="eng">Copy track as is</description>
<description lang="ger">Track 1:1 kopieren</description>
</outputSettings>
<outputSettings name="lpcm" outputFormat="LPCM-raw">
<description lang="eng">Save as raw LPCM</description>
<description lang="ger">Als RAW LPCM speichern</description>
</outputSettings>
<outputSettings name="wavex" outputFormat="LPCM-wavex">
<description lang="eng">Save as LPCM in WAV container</description>
<description lang="ger">Als LPCM im WAV-Container speichern</description>
</outputSettings>
<outputSettings name="flac-best" outputFormat="FLAC">
<description lang="eng">Save as FLAC (best compression)</description>
<description lang="ger">Als FLAC speichern (höchste Komprimierungsstufe)</description>
<extraArgs>-compression_level 12</extraArgs>
</outputSettings>
<outputSettings name="flac-fast" outputFormat="FLAC">
<description lang="eng">Save as FLAC (fast compression)</description>
<extraArgs>-compression_level 5</extraArgs>
</outputSettings>
<!-- Default rule - copy as is -->
<trackSettings input="default">
<output outputSettingsName="copy"
defaultSelection="$app_DefaultSelectionString">
</output>
</trackSettings>
<!-- Save LPCM mono or stereo as raw LPCM -->
<trackSettings input="LPCM-stereo">
<output outputSettingsName="flac-best"
defaultSelection="$app_DefaultSelectionString">
</output>
</trackSettings>
<!-- Put multi-channel LPCM into WAVEX container-->
<trackSettings input="LPCM-multi">
<output outputSettingsName="flac-fast"
defaultSelection="$app_DefaultSelectionString">
</output>
</trackSettings>
</profile>
I will say though, that I only convert PCM tracks to FLAC.
Since Media Center can decode DTS-HD and TrueHD anyway, it didn't seem worth the extra time to save ~1GB - though I will admit, I haven't really timed MakeMKV doing this.
There is additional downmix metadata which these formats store that Media Center may some day be capable of reading. (I think MakeMKV preserves this?)
In my entire library, it would probably free up the space for less than ten more films, so I'd rather just leave it in the original format for now. It wouldn't be difficult to convert at a later date.