Being in a flexed position at the hip and knee joints, then adding repetitive up and down movements (plantar and dorsiflexion) as well as some inversiom and eversion at the ankles when shifting gears and braking will for surely cause discomfort in many people.
Issues that come up:
Posture (how you are sitting and what your alignment is like)
Strength (which muscles are stronger and weaker and how it can have an effect on your joints
Flexibilty (how tight or loose are your big and small muscles - more specifically from the waist down)
Suppleness (are your joints and muscles naturally or "artificially" stiff, crunchy, grindy, clicky or do they glide past each other comfortably)
I know that certain bikes I have been on (mostly as a passenger) have given me serious pain, tingling, numbness and even swelling and lack of function after certain periods of time and routes in my legs and knees, ankles and toes. Like buying shoes or mattress - you gotta find the right fit for your body (which I am sure most of you have researched lots when buying your bikes) but you also have to take into account that it is quite physical and you should "warm-up" or stretch often and shake out your legs (some people have hand issues when riding - same goes) I would also say that adding daily stretching to your riding is important if you are noticing issues. It only takes a few minutes and it doesn't cost you a visit or time to the physio. For more complicated matters like previous accident or injury, I say it's always worth getting checked by a professional that suits your needs and wants whether it be massage, physio, chiro, kinies, etc etc and being hydrated as well some supplements as someone else already mentioned can go a long way for some people.
:flashy Good Luck!