It's hard to say no when you're a people pleaser. It's hard to say no when you feel a sense of expectation or obligation. It's hard to say no when you desperately desire to be liked, loved, or validated by another human being.
Once upon a time, I found saying "no" to be a much-dreaded task; now, I find it utterly liberating.
To be clear, I don't expect any of us to say "no" to everything -- that would be extremely selfish. To cultivate a spirit of gratitude and generosity, we must also be willing to "do unto others as we want done unto us", which means saying yes to requests and opportunities to serve (volunteering time and energy to varying causes, helping others with problem-solving needs, etc) when possible. The key is learning how to balance your yes or no responses appropriately.
It's easier to know when to say yes -- a health emergency in the family and money needs to be pooled together for medical bills; a friend applying for new job postings in need of people to list as references on his/her CV; a supervisor asking you to complete a work task clearly outlined in your job description as part of your responsibilities. On the other hand, it can prove much more difficult to know when it is "right" to say no.
With that being said, instinct is a wonderful thing.
I have learned to rely on it much more now than I ever did in the past. When someone asks something of me, I usually take a moment to check within myself to determine if my initial reaction is an easy yes and I feel at peace. If I don't and instead feel conflicted or unhappy for a prolonged period about it, then 9 out of 10 times it means I should respond with a "no". I give a great example in the post STORYTIME: How I Almost Got Expelled From University when I should have responded with a no, not yes.
In many instances, a "no" is required for ones physical, emotional, and mental health / wellbeing.
The truth is you cannot be everything to everybody; you're only one person. This truth will not always sit well with folks and that is A-OK. There will never be a time when you can please all people; the more you try, the more frustrated and resentful you're likely to become. Now I can't tell you when or when not to respond with a yes or no in your life; however, I can tell you that from personal experience, the sooner you start exercising your "no" muscle, the more courageous and happier you'll find yourself to be, with your sanity intact...ideally :)