I highly recommend a hardcore/Iron man mode with various mods such as USI life support, Remote tech.
And some house rules
such as:
no discovery before telescope observation (cacteye mod)
no manned missions over 1 day unless viable communications infrastructure (remote tech)
building vessels requires some x amount of days (I go between 3 - 10)
Each kerbal needs a rest time after missions (I go between 1 - 10)
No mechjeb, maybe kOs or remote tech integrated system
each science tree advancement can be used 10 days later
obviously no stock or pre-built crafts
simulations only allowed on a clone savegame
And if you want further challenge, you can try USI kolonization mod" and set a full system kolonization goal.
It's my second go through with these house rules, and first with these mods.. I'm having a blast of a time.. Really...
Each launch matters. I actually keep (have to) spreadsheets with active programs / ended programs, launch schedules, return to duty dates of Kerbanauts...
Combined with my newly discovered mods and kerbanaut specialties, it becomes a real challenge. Have to plan my programs, launches, investments in detail / ahead.
I mean, I love just building the max dv vessel and just hitting the road on sandbox. But even achieving a simple duna mission on this mode becomes full satisfaction.
And, I have only 5 - 10 hours of time to spare every week (a "little" bit more these days - recently unemployed and relaxing) and the so called "completion" of the game with active Space stations etc. seems minimum 300 hours ahead if not more... So, it will take around a year, and this makes every launch important and enjoyable, every new design matters - instead of rushing towards the end..
existentially speaking: what's the end point.. We complete this task, then something else comes. we cook, eat, it becomes a task, we sleep, wake up, shower, go to work, and something else comes.. tasks never end.. And life becomes a list of errands. Going through everything? where's the end point? existentially speaking: not being... So, what it takes to make a life significant in ones own eyes is merely enjoying the simple steps... Nothing else remains. If we keep our eyes on the finish line as they say, we all know where the ultimate finish line is.. But, a good climber never stares at the peak, a good athlete never stares at his watch while practicing. While planning big - living with small goals, and small rewards is what takes us to long term results in a satisfying way... Since, if we keep our eyes on the finish line, we all know where the ultimate finish line is...